Pyrazolopyrimidine compounds

ABSTRACT

The present teachings provide a compound represented by structural formula (I-0), or a pharmaceutically acceptable salt thereof. Also described are pharmaceutical compositions and methods of use thereof.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/727,581, filed Nov. 16, 2012. This application also claims the benefit of U.S. Provisional Application No. 61/808,152, filed Apr. 3, 2013. The entire teachings of these two applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Protein kinases have been the subject of extensive study in the search for new therapeutic agents in various diseases, for example, cancer. Protein kinases are known to mediate intracellular signal transduction by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell.

Human TTK protein kinase (TTK), also known as tyrosine threonine kinase, dual specificity protein kinase TTK, Monopolar Spindle 1 (Mps1) and Phosphotyrosine-Picked Threonine Kinase (PYT), is a conserved multispecific kinase that is capable of phosphorylating serine, threonine and tyrosine residues when expressed in E. coli (Mills et al., J. Biol. Chem. 22(5): 16000-16006 (1992)). TTK mRNA is not expressed in the majority of physiologically normal tissues in human (Id). TTK mRNA is expressed in some rapidly proliferating tissues, such as testis and thymus, as well as in some tumors (for example, TTK mRNA was not expressed in renal cell carcinoma, was expressed in 50% of breast cancer samples, was expressed in testicular tumors and ovarian cancer samples) (Id). TTK is expressed in some cancer cell lines and tumors relative to normal counterparts (Id.; see also WO 02/068444 A1).

Therefore, agents which inhibit a protein kinase, in particular TTK, have the potential to treat cancer. There is a need for additional agents which can act as protein kinase inhibitors, in particular TTK inhibitors.

In addition, cancer recurrence, drug resistance or metastasis is one of the major challenges in cancer therapies. Cancer patients who responded favorably to the initial anti-cancer therapy often develop drug resistance and secondary tumors that lead to the relapse of the disease. Recent research evidences suggest that the capability of a tumor to grow and propagate is dependent on a small subset of cells within the tumor. These cells are termed tumor-initiating cells (TICs) or cancer stem cells. It is thought that the TICs are responsible for drug resistance, cancer relapse and metastasis. Compounds that can inhibit the growth and survival of these tumor-initiating cells can be used to treat cancer, metastasis or prevent recurrence of cancer. Therefore, a need exists for new compounds that can inhibit the growth and survival of tumor-imitating cells.

SUMMARY OF THE INVENTION

Applicants have now discovered that certain pyrazolotriazine and pyrazolopyrimidine compounds are potent kinase inhibitors, such as TTK protein kinase (see Example B). Applicants have also discovered that these compounds have potent anticancer activity against pancreatic cancer, prostate cancer, lung cancer, melanoma, breast cancer, colon cancer, and ovarian cancer cells in cell culture study (see Examples C-D). Based on these discoveries, pyrazolotriazine and pyrazolopyrimidine compounds, pharmaceutical compositions thereof, and methods of treating cancer with the pyrazolotriazine and pyrazolopyrimidine compounds are disclosed herein.

The present teachings are directed, at least in part, to a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Y is N or CH;

R is phenyl or monocyclic 5-6 membered heteroaryl, both of which are substituted with —C(═O)NR^(d)R^(e) or —NHC(═O)R⁵, —C(═S)NR^(d)R^(e), or —NHC(═S)R⁵ and optionally substituted with one or more groups selected from one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, and (C₁-C₃)haloalkoxy;

R¹ is —NR^(a1)R^(b1), —OR^(c1), —SR^(c1), —SOR^(c1), or —SO₂R^(c1);

R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl;

R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(a1) and R^(b1) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(a1) and R^(b1), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring;

R^(a2) and R^(b2) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(a2) and R^(b2), together with the nitrogen to which they are attached, form an optionally substituted 3-8 membered ring (e.g., a bridged bicyclic ring);

R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(d) and R^(e) are each independently selected from —H, optionally substituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(d) and R^(e), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring.

In one embodiment, the present teachings include a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by structural formula (I-0) described above or a pharmaceutically acceptable salt thereof.

In another embodiment, the present teachings provide a method of treating a subject having cancer comprising administering to the subject an effective amount of a compound of structural formula (I-0) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present teachings provides a method of inhibiting TTK activity in a subject in need of inhibition of TTK activity, comprising administering to the subject an effective amount of a compound represented by Structural Formula (I-0) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present teachings includes the use of a compound represented by Structural Formula (I-0) or a pharmaceutically acceptable salt thereof in therapy. In some embodiments, the therapy is for treating a subject with cancer. Alternatively, the therapy is for inhibiting TTK activity in a subject in need of inhibition of TTK activity.

Another embodiment of the present teachings includes the use of a compound represented by Structural Formula (I-0) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with cancer.

Another embodiment of the present teachings includes the use of a compound represented by Structural Formulas (I-0) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting TTK activity in a subject in need of inhibition of TTK activity.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present teachings are directed to a compound represented by Structural Formula (I-0) or a pharmaceutically acceptable salt thereof; and values and alternative values for the variables in Structural Formula (I-0) are provided in the following paragraphs:

In a first embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Y is N or CH;

R is phenyl or monocyclic 5-6 membered heteroaryl, both of which are substituted with —C(═O)NR^(d)R^(e) or —NHC(═O)R⁵, and optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, and (C₁-C₃)haloalkoxy;

R¹ is —NR^(a1)R^(b1) or —OR^(c1);

R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;

R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(a1) and R^(b1) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl;

R^(a2) and R^(b2) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(a2) and R^(b2), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring;

R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl; and

R^(d) and R^(e) are each independently selected from —H, optionally substituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(d) and R^(e), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring.

In a second embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

R is phenyl or monocyclic 5-6 membered heteroaryl, both of which are substituted with —C(═O)NR^(d)R^(e), —NHC(═O)R⁵, —C(═S)NR^(d)R^(e), or —NHC(═S)R⁵ and optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, and (C₁-C₃)haloalkoxy;

R¹ is —NR^(a1)R^(b1), —OR^(c1), —SR^(c1), —SOR^(c1), or —SO₂R^(c1);

R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;

R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(a1) and R^(b1) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl;

R^(a2) and R^(b2) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(a2) and R^(b2), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring;

R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇) cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl;

R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl; and

R^(d) and R^(e) are each independently selected from —H, optionally substituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or

R^(d) and R^(e), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring.

In a third embodiment, the compound is represented by structural formula:

or a pharmaceutically acceptable salt thereof, wherein R³ is —C(═O)NR^(d)R^(e) or NHC(═O)R⁵; each R⁴ is independently selected from hydrogen, halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and m is 1, 2, or 3; and values for the remainder of the variables are as described for Structural Formula (I) or in the second embodiment.

In a fourth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values for the remainder of the variables are as described for Structural Formula (I-0), (I), or (I)′, or in the first, second, or third embodiment.

In a fifth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein X is NH or O; R⁵ is selected from (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; R¹¹ is (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, —C(═O)NH₂, —C(═O)NH(C₁-C₃)alkyl, —C(═O)N((C₁-C₃)alkyl)₂, and —SO₂(C₁-C₃)alkyl; R^(d) is independently selected from —H, (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 4-5 membered heterocycloalkyl wherein each of the (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, and 4-5 membered heterocycloalkyl is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; n is 0, 1, 2, or 3; and values and alternative values for the remainder of the variables are as described for Structural Formula (I) or in the second or third embodiment.

In a sixth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values and alternative values for the remainder of the variables are as described for Structural Formula (I) or in the second, third, or fifth embodiment.

In a seventh embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, or fifth embodiment.

In an eighth embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2), R^(b2) is —H or CH₃; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, or fifth embodiment.

In a ninth embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2), R^(a2) is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl (preferably, 3-7 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl); wherein each of which is optionally substituted with one or more groups selected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃)hydroxyalkyl, 3-7 membered monocyclic heterocycloalkyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, fifth, or eighth embodiment.

In a tenth embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2), R^(a2) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl, pyridyl, or phenyl (preferably, methyl, propyl, butyl, pentyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl; more preferably, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl, pyridyl, or phenyl), wherein each of the methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl, pyridyl, and phenyl (preferably, methyl, propyl, butyl, pentyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl; more preferably, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl, pyridyl, or phenyl) is optionally substituted with one or more groups selected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, and oxetanyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, fifth, eighth or ninth embodiment.

In an eleventh embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2), R^(a2) and R^(b2), together with the nitrogen to which they are attached, form a 3-7 membered monocyclic heterocycloalkyl, optionally substituted with one or more groups selected from halogen, CN, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)(C₁-C₃)alkyl, and 3-7 membered monocyclic heterocycloalkyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, or fifth embodiment.

Alternatively, R^(a2) and R^(b2), together with the nitrogen to which they are attached, form piperidinyl, morpholinyl, or piperazinyl (preferably, morpholinyl), wherein each substitutable carbon atom in the piperidinyl, morpholinyl, or piperazinyl (preferably, morpholinyl) is optionally substituted with halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxyalkyl or (C₁-C₃)alkoxy; and each substitutable nitrogen atom in the piperazinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₃-C₅)cycloalkyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, oxetanyl, or —C(═O)H.

In a twelfth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, fifth, or sixth embodiment.

In a thirteen embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-D1), or (II-A2), R^(c2) is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl (preferably, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl), each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)H, and 3-7 membered monocyclic heterocycloalkyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, or fifth embodiment.

In a fourteenth embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-D1), or (II-A2), R^(c2) is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or azetidinyl (preferably, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl; more preferably, tetrahydro-2H-pyranyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or azetidinyl), wherein each substitutable carbon atom in the cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azetidinyl (preferably, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, and piperidinyl; more preferably, tetrahydro-2H-pyranyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, and azetidinyl) is optionally substituted with one or more groups selected from halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, oxetanyl; and each substitutable nitrogen atom in the azetidinyl, pyrrolidinyl, or piperidinyl, is optionally substituted with (C₁-C₃)alkyl, (C₃-C₅)heterocycloalkyl, (C₁-C₃)hydroxylalkyl, C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₅)cycloalkyl, or —C(═O)H; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the second, third, fifth, or thirteenth embodiment.

In a fifteenth embodiment, for compounds represented by any one of structural formulae (I-A), (II-A1), (II-B1), (II-C1), (II-D1), or (II-A2), R⁴ is selected from hydrogen, halogen, and (C₁-C₃)alkyl (preferably, R⁴ is chlorine or methyl; and is ortho to —C(═O)NR^(d)R^(e)); and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the third, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

In a sixteenth embodiment, for compounds represented by any one of structural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), (II-D1), or (II-A2), R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl (preferably, R^(d) is cyclopropyl), wherein both of which are optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the third, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

In a seventeenth embodiment, for compounds represented by any one of structural formulae (II-A1), (II-B1), (II-C1), (II-D1), or (II-A2), R¹¹ is (C₁-C₆)alkoxy, ethyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl (preferably, methoxy, ethyl, isopropyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, pyridinyl, or oxetanyl), wherein each substitutable carbon atom in the ethyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, and oxetanyl (preferably, methoxy, ethyl, isopropyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, pyridinyl, or oxetanyl) is optionally substituted with halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen atom in the piperazinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, oxetanyl, tetrahydro-2H-pyranyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, or —C(═O)H; and values and alternative values for the remainder of the variables are as described for Structural Formula (I), or in the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

In a eighteenth embodiment, for compounds represented by any one of structural formulae (I-0), (I), (I)′, (I-A), or (II-A0), R¹ is —NHR^(b1), R^(b1) is (C₁-C₄)alkyl optionally substituted with one or more groups selected from hydroxy, (C₁-C₃)alkoxy, hydroxy(C₁-C₃)alkyl, —SO₂(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, or 3-7 membered heterocycloalkyl containing one ring heteroatom, the heteroatom being oxygen, wherein the (C₃-C₇)cycloalkyl or the 3-7 membered heterocycloalkyl substituent is optionally substituted with halogen, hydroxyl, or (C₁-C₃)alkyl; alternatively, R^(b1) is (C₁-C₄)alkyl optionally substituted with one or more groups selected from hydroxy, (C₁-C₃)alkoxy, hydroxymethyl, —SO₂(C₁-C₃)alkyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the cyclobutyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl substituent is optionally substituted with 1-2 groups selected from hydroxy or (C₁-C₃)alkyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I-0), (I), or (I)′, or in the first, second, third, or fourth embodiment.

Preferably in the eighteenth embodiment, R¹ is represented by the one of the following structural formulae:

In a nineteenth embodiment, for compounds represented by any one of structural formulae (I-0), (I), (I)′, (I-A), or (II-A0), R¹ is —NHR^(b1), R^(b1) is (C₁-C₄)alkyl optionally substituted with one or more groups selected from i) 4-6 membered heterocycloalkyl substituted with —N(R^(a1))₂, wherein the heterocycloalkyl contains one ring heteroatom which is oxygen; ii) —N(R^(a1))₂; iii) 4-6 membered heterocycloalkyl containing one ring heteroatom which is nitrogen; or iv) 5-6 membered nitrogen-containing heteroaryl; wherein R^(a1) is H or (C₁-C₃)alkyl; and the 4-6 membered heterocycloalkyl or 5-6 membered nitrogen-containing heteroaryl substituent is optionally substituted with one or more groups selected from (C₁-C₃)alkyl, hydroxy, halogen, —NH₂, —NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂; alternatively, R^(b1) is (C₁-C₄)alkyl optionally substituted with one or more groups selected from tetrahydropyranyl substituted with —N(R^(a1))₂; N(R^(a1))₂; morpholinyl; piperazinyl; piperidinyl; pyridinyl; and imidazolyl; wherein the morpholinyl, piperazinyl, piperidinyl, pyridinyl, or imidazolyl substituent is optionally substituted with 1-2 groups selected from (C₁-C₃)alkyl, halo, or hydroxyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I-0), (I), or (I)′, or in the first, second, third, or fourth embodiment.

Preferably in the nineteenth embodiment, R¹ is represented by the one of the following structural formulae:

In a twentieth embodiment, for compounds represented by any one of structural formulae (I-0), (I), (I)′, (I-A), (II-A0), (II-A1), (II-A2), or (II-B1), R² is R^(c2) or —OR^(c2), and R^(c2) is (C₃-C₇)cycloalkyl; 4-7 membered heterocycloalkyl containing one ring heteroatom which is oxygen; phenyl; or 5-6 membered nitrogen-containing heteroaryl; each of which is optionally substituted with halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, or —SO₂(C₁-C₃)alkyl; alternatively, R^(c2) is cyclobutyl, cyclopentyl, cyclohexanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrazolyl, or pyridyl-N-oxide, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, —SO₂(C₁-C₃)alkyl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I-0), (I), or (I)′, or in the first, second, third, fourth, eighteenth, or nineteenth embodiment.

Preferably in the twentieth embodiment, R² is represented by the one of the following structural formulae:

In a twenty first embodiment, for compounds represented by any one of structural formulae (I-0), (I), (I)′, (I-A), (II-A0), (II-A1), (II-A2), or (II-B1), R² is

4-10 membered heterocycloalkyl containing one ring heteroatom which is nitrogen optionally substituted with hydroxy, hydroxy(C₁-C₃)alkyl, —C(═O)(C₁-C₃)alkyl, or (C₃-C₇)cycloalkyl;

5-10 membered nitrogen-containing heteroaryl;

OR^(c2), wherein R^(c2) is phenyl optionally substituted with halogen, (C₁-C₃)alkyl, —N(R^(a1))₂ or 4-6 membered heterocycloalkyl containing one ring heteroatom which is nitrogen; pyridinyl optionally substituted with halogen or (C₁-C₃)alkyl; piperidinyl optionally substituted with 4-6 membered heterocycloalkyl containing one ring heteroatom which is oxygen, or (C₁-C₃)alkoxy; pyrrolidinyl optionally substituted with 4-6 membered heterocycloalkyl containing one ring heteroatom which is oxygen or (C₁-C₃)alkoxy; or azetidinyl optionally substituted with 4-6 membered heterocycloalkyl containing one ring heteroatom which is oxygen or (C₁-C₃)alkoxy; wherein R^(a1) is H or (C₁-C₃)alkyl, or

NHR^(b2) or N((C₁-C₃)alkyl)R^(b2) wherein R^(b2) is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered heterocycloalkyl containing one ring heteroatom which is oxygen, phenyl, or 5-6 membered nitrogen-containing heteroaryl;

-   -   wherein the (C₁-C₄)alkyl represented by R^(b2) is optionally         substituted with one or more groups selected from hydroxy,         —C(═O)NH₂, (C₁-C₄)alkyl, hydroxy(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl,         3-7 membered heterocycloalkyl containing one ring heteroatom         which is oxygen, and wherein the (C₃-C₇)cycloalkyl, 3-7 membered         heterocycloalkyl, phenyl, and 5-6 membered nitrogen-containing         heteroaryl substituents in the group represented by R^(b2) are         optionally substituted with hydroxy, halogen, (C₁-C₃)alkyl,         (C₁-C₃)alkoxy, hydroxy(C₁-C₃)alkyl.

Alternatively in the twenty first embodiment, R² is

azetidinyl optionally substituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl; pyrrolidinyl optionally substituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl; piperidinyl optionally substituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl; piperazinyl optionally substituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl; morpholinyl optionally substituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl;

pyridinyl, quinolinyl,

OR^(c2), wherein R^(c2) is phenyl optionally substituted with —N(R^(a1))₂ or with 4-6 membered heterocycloalkyl with one ring heteroatom which is nitrogen; pyridinyl optionally substituted with halogen; piperidinyl optionally substituted with oxetanyl; or pyrrolidinyl optionally substituted with oxetanyl; wherein R^(a1) is H or (C₁-C₃)alkyl;

—NH-cyclopentyl, —N—((C₁-C₃)alkyl)-cyclopentyl or NHR^(b2), wherein R^(b2) is phenyl or pyridinyl, each of which is optionally substituted with halo or (C₁-C₃)alkyl;

cyclopropyl optionally substituted with hydroxyl, hydroxymethyl, or oxetanyl; cyclobutyl optionally substituted with hydroxyl, hydroxymethyl, or oxetanyl; cyclopentyl optionally substituted with hydroxyl, hydroxymethyl, or oxetanyl; cyclohexanyl optionally substituted with hydroxyl, hydroxymethyl, or oxetanyl;

tetrahydropyranyl optionally substituted with hydroxyl or hydroxymethyl, tetrahydrofuranyl optionally substituted with hydroxyl or (C₁-C₃)alkoxy; oxetanyl; or

(C₁-C₄)alkyl, wherein the (C₁-C₄)alkyl is optionally substituted with one or more groups selected from hydroxy, —C(═O)NH₂, (C₁-C₄)alkoxy, hydroxy(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, 3-6 membered heterocycloalkyl containing one ring heteroatom which is oxygen; and values and alternative values for the remainder of the variables are as described for Structural Formula (I-0), (I), or (I)′, or in the first, second, third, fourth, eighteenth, or nineteenth embodiment.

Preferably in the twenty first embodiment, R² is represented by the one of the following structural formulae:

In a twenty second embodiment, for compounds represented by structural formula (I-0) or (II-A0), R² is R¹ is —NH—(CH₂)_(x)—Cy, wherein x is 1 or 2, and Cy is morpholinyl or piperidinyl optionally substituted with (C₁-C₃)alkyl or F; and R² is —O-phenyl optionally substituted with one or two F. Alternatively, R¹ is —NH—(CH₂)_(x)—Cy, wherein x is 1 or 2, and Cy is —N-morpholinyl, -piperidyl N-substituted with (C₁-C₃)alkyl or —N-piperidyl optionally substituted with fluorine; and R² is —O-phenyl optionally substituted with one or two F. Alternatively, R¹ is —NH—CH₂—Cy, wherein Cy is C₃-C₄ cycloalkyl optionally substituted with one or two groups selected from alkyl and hydroxyl; or 4-6 membered heterocycloalkyl containing one ring heteroatom atom which is oxygen; and R² is —O-pyridinyl; —NH—(C₂-C₆)hydroxyalkyl optionally substituted with cyclopropyl or isopropyl; or —NH—(C₃-C₆)cycloalkyl optionally substituted with hydroxyl or (C₁-C₂)hydroxylalkyl. Values and alternative values for the remainder of the variables are as described for Structural Formula (I-0).

Alternatively for the 22^(nd) embodiment, the following compounds or pharmaceutically acceptable salts thereof are excluded:

In a twenty third embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R³ is —C(═O)NR^(d)R^(e) or —NHC(═O)R⁵; each R⁴ is independently selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and m is 0, 1, 2, or 3; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′.

In a twenty fourth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is NH or O;

R⁵ is selected from (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy;

R¹¹ is (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, —C(═O)NH₂, and —SO₂CH₃;

R^(d) and R^(e) are each independently selected from —H, (C₁-C₇)alkyl, (C₃-C₇) cycloalkyl, wherein each of the (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and

n is 0, 1, 2, or 3;

and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′ or in the twenty third embodiment.

In a twenty fifth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′ or in the twenty third or twenty fourth embodiment.

In a twenty sixth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′ or in the first, twenty third, twenty fourth, or twenty fifth embodiment.

In a twenty seventh embodiment, for compounds represented by any one of structural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, or (II-A2)′, R^(b2) is —H or CH₃; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, twenty fifth, or twenty sixth embodiment.

In a twenty eighth embodiment, for compounds represented by any one of structural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, or (II-A2)′, R² is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl; wherein each of which is optionally substituted with one or more groups selected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; alternatively, R^(a2) is methyl, ethyl, t-butyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, pyridyl, or phenyl, wherein each of the cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, pyridyl, and phenyl is optionally substituted with one or more groups selected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, twenty fifth, twenty sixth, or twenty seventh embodiment.

In a twenty ninth embodiment, for compounds represented by any one of structural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, or (II-A2)′, R^(a2) and R^(b2), together with the nitrogen to which they are attached, form a 3-7 membered monocyclic heterocycloalkyl, optionally substituted with one or more groups selected from halogen, CN, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)(C₁-C₃)alkyl, and 3-7 membered monocyclic heterocycloalkyl; alternatively, R^(a2) and R^(b2), together with the nitrogen to which they are attached, form piperidinyl, morpholinyl, or piperazinyl, wherein each substitutable carbon atom in the piperidinyl, morpholinyl, or piperazinyl is optionally substituted with halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen atom in the piperazinyl is optionally substituted (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, oxetanyl, or —C(═O)H; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, twenty fifth, twenty sixth, or twenty seventh embodiment.

In a thirtieth embodiment, the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, or twenty fifth embodiment.

In a thirty first embodiment, for compounds represented by any one of structural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-D1)′, or (II-A2)′, R^(c2) is (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₇)cycloalkyl, and —C(═O)H; alternatively, R^(c2) is cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, or azetidinyl, wherein each of the cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, and pyridyl is optionally substituted with one or more groups selected from halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, and (C₁-C₃)alkoxy; and the nitrogen in the azetidinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₅)cycloalkyl, or —C(═O)H; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, or twenty fifth embodiment.

In a thirty second embodiment, for compounds represented by any one of structural formulae (II-A1)-(II-D1), (II-A1)′-(II-D1)′, (II-A2), or (II-A2)′, X is NH; and values and alternative values for the remainder of the variables are as described for Structural Formula (I) or (I)′, or in the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, twenty fourth, twenty fifth, twenty sixth, twenty seventh, twenty eighth, twenty ninth, thirtieth, or thirty first embodiment. Alternatively, X is O.

In a thirty third embodiment, for compounds represented by any one of structural formulae (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, (II-D1)′, or (II-A2)′, R⁴ is selected from hydrogen, halogen, and (C₁-C₃)alkyl (preferably, R⁴ is chlorine or methyl; and is ortho to —C(═O)NR^(d)R^(e)); and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the twenty third, twenty fourth, twenty fifth, twenty sixth, twenty seventh, twenty eighth, twenty ninth, thirtieth, thirty first, thirty second embodiment.

In a thirty fourth embodiment, for compounds represented by any one of structural formulae (II-A1)′, (II-B1)′, or (II-A2)′, R¹¹—(CH₂)_(n)—X— is represented by the one of the following structural formulae:

and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, or twenty fifth embodiment.

In a thirty fifth embodiment, for compounds represented by any one of structural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, or (II-A2)′, R² is represented by the one of the following structural formulae:

and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, or in the first, twenty third, twenty fourth, or twenty fifth embodiment.

In a thirty sixth embodiment, for compounds represented by any one of structural formulae (I-0), (I), (I)′, (I-A), (I-A)′, (II-A0), (II-A1)′, (II-B1)′, or (II-A2)′, R⁴ is selected from hydrogen, halogen, and (C₁-C₃)alkyl (preferably, R⁴ is chlorine or methyl; and is ortho to —C(═O)NR^(d)R^(e)); and values and alternative values for the remainder of the variables are as described for Structural Formula (I-0), (I), (I)′, (I-A), (II-A0), or in the eighteenth, nineteenth, twentieth, twenty first, twenty second, twenty third, twenty fourth, twenty fifth, thirty fourth, or thirty fifth embodiment.

In a thirty seventh embodiment, for compounds represented by any one of structural formulae (II-A1)′, (II-B1)′, (II-C1)′, (II-D1)′, or (II-A2)′, R¹¹ is ethyl, isopropyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl, wherein each substitutable carbon in the morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl is optionally substituted with —OH, halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen in the piperazinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, or —C(═O)H; alternatively, R¹¹ is isopropyl, morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl, wherein each substitutable carbon in the morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl is optionally substituted with halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen in the piperazinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, or —C(═O)H; and values and alternative values for the remainder of the variables are as described for Structural Formula (I)′, (I-A)′, (II-A0), or in the twenty fourth, twenty fifth, twenty sixth, twenty seventh, twenty eighth, twenty ninth, thirtieth, thirty first, or thirty second embodiment.

In a thirty eighth embodiment, for compounds represented by any one of structural formulae (I)′, (I), (I-A), (I-A)′, (II-A1)-(II-D), (II-A1)′-(II-D1)′, (II-A2) or (II-A2)′, R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl, wherein both of which are optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy (preferably, R^(d) is cyclopropyl); and values and alternative values for the remainder of the variables are as described for Structural Formula (I), (I)′, or in the third, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, twenty third, twenty fourth, twenty fifth, twenty sixth, twenty seventh, twenty eighth, twenty ninth, thirtieth, thirty first, thirty second, thirty third, or thirty seventh embodiment.

In a thirty ninth embodiment, for compounds represented by structural formula (II-A0), R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl, wherein both of which are optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy (preferably, R^(d) is cyclopropyl); and values and alternative values for the remainder of the variables are as described for Structural Formula (I-0), (I), (I)′, (I-A), or in the seventeenth, eighteenth, nineteenth, twentieth, twenty first, thirty fourth, or thirty fifth embodiment.

The invention also includes the compounds depicted by structure and/or described by name in the Exemplification, and includes both the neutral forms and as well as pharmaceutically acceptable salts thereof. Treatments with and/or uses of these compounds (including neutral forms and pharmaceutically acceptable salts thereof) as described herein are also included in the invention.

The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “cycloalkyl”, “heterocycloalkyl”, “aralkyl”, “heteroaralkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e., (C₁-C₆)alkyl. As used herein, a “(C₁-C₆)alkyl” group is means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by —O-alkyl. For example, “(C₁-C₃)alkoxy” includes methoxy, ethoxy, and propoxy.

The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br or I. Preferably the halogen in a haloalkyl or haloalkoxy is F or Cl.

The term “ring” used herein means a cyclic group, which includes cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. It can be monocyclic, bicyclic (e.g., a bridged bicyclic ring), polycyclic (e.g., tricyclic), or fused.

The term “aryl group” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, means an aromatic hydrocarbon ring system having six to fourteen carbon ring atoms. The term “aryl” may be used interchangeably with the terms “aryl ring” “aromatic ring”, “aryl group” and “aromatic group”. An aryl group typically has six to fourteen ring atoms. Examples includes phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. A “substituted aryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon atom bonded to a hydrogen.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radical optionally containing one or more double bonds. It can be monocyclic, bicyclic (e.g., a bridged bicyclic ring), polycyclic (e.g., tricyclic), or fused. For example, monocyclic (C₃-C₇)cycloalkyl means a radical having from 3-7 carbon atoms arranged in a monocyclic ring. A (C₃-C₇)cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

“Heterocycloalkyl” means a saturated or unsaturated non-aromatic 3-12 membered ring radical optionally containing one or more double bonds. It can be monocyclic, bicyclic (e.g., a bridged bicyclic ring), tricyclic, or fused. The heterocycloalkyl contains 1 to 4 heteroatoms, which may be the same or different, selected from N, O or S. The heterocycloalkyl ring optionally contains one or more double bonds and/or is optionally fused with one or more aromatic rings (e.g., phenyl ring). “3-7 membered monocyclic heterocycloalkyl” means a radical having from 3-7 atoms (including 1-3 heteroatoms) arranged in a monocyclic ring. The term “heterocycloalkyl” is intended to include all the possible isomeric forms. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group”, “heteroaromatic ring”, and “heteroaromatic group”, are used interchangeably herein. “Heteroaryl” when used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). “Heteroaryl” includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. As such, “5-14 membered heteroaryl” includes monocyclic, bicyclic or tricyclic ring systems.

“Monocyclic 5-6 membered heteroaryl” means a monocyclic aromatic ring system having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, or benzisoxazolyl. A “substituted heteroaryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.

Unless otherwise indicated, suitable substituents for a substituted alkyl, cycloalkyl, heterocycloalkyl, aryl group (e.g., phenyl) and heteroaryl group include the groups represented by halogen, —OR^(c), —NR^(a)R^(b), —S(O)_(i)R^(c), —NR^(d1)S(O)_(i)R^(c), —S(O)_(i)NR^(e1)R^(f), —C(═O)OR^(c), —OC(═O)OR^(c), —C(═S)OR^(c), —O(C═S)R^(c), —C(═O)NR^(e1)R^(f), —NR^(d1)C(═O)R^(c), —C(═S)NR^(e1)R^(d), —NR^(d1)C(═S)R^(c), —NR^(d1)(C═O)OR^(c), —O(C═O)NR^(e1)R^(f), —NR^(d1)(C═S)OR^(c), —O(C═S)NR^(e1)R^(f), —NR^(d1)(C═O)NR^(e1)R^(f), —NR^(d1)(C═S)NR^(e1)R^(f), —C(═S)R^(c), —C(═O)R^(c), (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₃)alkyl, heterocycloalkyl, heterocycloalkyl(C₁-C₃)alkyl, aryl, aryl(C₁-C₃)alkyl, heteroaryl and heteroaryl(C₁-C₃)alkyl, wherein:

“cycloalkyl” and “heterocylalkyl” include spiro and as well as cycloalkyl and heterocycloalkyl connected by a single bond to the core of the molecule.

The term “spiro” refers to a cycloalkyl or heterocycloalkyl that shares one ring carbon atom with another cycloalkyl or heterocycloalkyl group in the molecule

R^(a) and R^(b) are each independently selected from —H and (C₁-C₆)alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy, —NR^(g)R^(h) and (C₁-C₃)alkoxy;

R^(c) is —H or (C₁-C₆)alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, —NR^(g)R^(h), hydroxy and (C₁-C₃)alkoxy;

R^(d1) is —H or (C₁-C₆)alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, —NR^(g)R^(h), hydroxy and (C₁-C₃)alkoxy;

R^(e1) and R^(f) are each independently selected from —H and (C₁-C₆)alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —NR^(g)R^(h), hydroxy and (C₁-C₃)alkoxy;

or R^(c1) and R^(f), together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from halogen, —NR^(g)R^(h), —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, and (C₁-C₃)alkoxy(C₁-C₆)alkyl;

R^(g) and R^(h) are each independently selected from —H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and (C₁-C₃)alkoxy(C₁-C₆)alkyl; and

i is 0, 1 or 2;

Unless otherwise indicated, in a preferred embodiment, suitable substituents for a substituted alkyl, cycloalkyl, heterocycloalkyl, aryl group (e.g., phenyl) and heteroaryl group include the groups represented by halogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy, —C(═O)NH₂, —SO₂CH₃, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl (e.g., —C(═O)(C₃-C₅)cycloalkyl), —C(═O)(C₁-C₃)alkyl, 3-7 membered monocyclic heterocycloalkyl (e.g., oxetanyl).

Unless otherwise indicated, in a preferred embodiment, when phenyl or monocyclic 5-6 membered heteroaryl is optionally substituted, suitable substituents are selected from halogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy, —C(═O)NH₂, and —SO₂CH₃.

Unless otherwise indicated, in a preferred embodiment, suitable substituents for a substituted alkyl, cycloalkyl, heterocycloalkyl include halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy and 3-7 membered monocyclic heterocycloalkyl (e.g., oxetanyl).

Regarding connectivity, an “arylalkyl” moiety, for example, refers to an alkyl group substituted with an aryl group (e.g., phenylmethyl (i.e., benzyl)). Similarly, a “heteroarylalkyl” moiety refers to an alkyl group substituted with a heteroaryl group.

Certain of the compounds described herein may exist in various stereoisomeric or tautomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. The present teachings encompass all such forms, including compounds in the form of essentially pure enantiomers, racemic mixtures and tautomers, which includes forms not depicted structurally. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, tautomers, geometric isomers or a combination thereof.

When a geometric isomer is depicted by name or structure, it is to be understood that the geometric isomeric purity of the named or depicted geometric isomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geometric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. The disclosed compounds have basic amine groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

Compounds described herein can inhibit various kinases, including the TTK. Thus, generally, compounds described herein are useful in the treatment of diseases or conditions associated with such kinases. In some embodiments, compounds described herein can inhibit TTK.

In one embodiment, the compounds described herein are TTK inhibitors, and are useful for treating diseases, such as cancer, associated with such kinase(s).

Another aspect of the present teachings relates to a method of treating a subject with cancer comprising administering to the subject an effective amount of a compound described herein. In one embodiment, the compounds described herein inhibit the growth of a tumor. For example, the compounds described herein inhibit the growth of a tumor that overexpresses TTK.

Cancers that can be treated (including reduction in the likelihood of recurrence) by the methods of the present teachings include lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma. In one embodiment, the cancer is selected from leukemia, acute myeloid leukemia, chronic myelogenous leukemia, breast cancer, brain cancer, colon cancer, colorectal cancer, head and neck cancer, hepatocellular carcinoma, lung adenocarcinoma, metastatic melanoma, pancreatic cancer, prostate cancer, ovarian cancer and renal cancer. In one embodiment, the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform or ovarian cancer. In another embodiment, the cancer is pancreatic cancer, prostate cancer, lung cancer, melanoma, breast cancer, colon cancer, or ovarian cancer. In yet another embodiment, the cancer is breast cancer, colon cancer and ovarian cancer. In yet another embodiment, the cancer is a breast cancer. In yet another embodiment, the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer. In yet another embodiment, the cancer is a basal sub-type breast cancer that overexpresses TTK. In yet another embodiment, the basal sub-type breast cancer is ER (estrogen receptor), HER2 and PR (progesterone receptor) negative breast cancer. In yet another embodiment, the cancer is a soft tissue cancer. A “soft tissue cancer” is an art-recognized term that encompasses tumors derived from any soft tissue of the body. Such soft tissue connects, supports, or surrounds various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissues, fatty tissue, blood and lymph vessels, perivascular tissue, nerves, mesenchymal cells and synovial tissues. Thus, soft tissue cancers can be of fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymph vessels, and fibrous tissues. Soft tissue cancers can be benign or malignant. Generally, malignant soft tissue cancers are referred to as sarcomas, or soft tissue sarcomas. There are many types of soft tissue tumors, including lipoma, lipoblastoma, hibernoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma, fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymomas, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small cell tumor. In a particular embodiment, the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a leiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma.

In some embodiments, the present teachings provide methods of inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject who is undergoing an anti-cancer therapy. The method comprises the steps of:

a) assessing the subject to determine whether the cancer is in remission; and

b) if the cancer is in remission; then administering to the subject an effective amount of a TTK inhibitor (e.g., a compound represented by Structural Formula (I-0), (I) or (I)′). If the cancer is not in remission, the method optionally further comprises the step of continuing the anti-cancer therapy until the cancer goes into remission and then the step b) of administering an effective amount of a TTK inhibitor (e.g., a compound represented by Structural Formula (I-0), (I) or (I)′).

As used herein, the term “tumor-initiating cells” or “TICs” refer to cells present within some tumors that possess the ability to self-renew and proliferate. These cells are sometimes called cancer stem cells (CSCs) and may be observed to share certain characteristics with normal stem cells, including a stem cell-like phenotype and function. In some embodiments, TICs are characterized by their ability to form tumors after xenotransplantation in immunodeficient mice.

In some embodiments, the present teachings provide methods of inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject whose cancer is in remission comprising administering to the subject an effective amount of a TTK inhibitor (e.g, a compound represented by Structural Formula (I-0), (I) or (I)′).

In some embodiments, e.g., where the subject is being treated to reduce the likelihood of recurrence of a cancer, the subject has already been treated with an anti-cancer therapy. Alternatively, the subject has already been treated with an anti-cancer therapy and the subject is in remission.

In some embodiments, the present teachings provide methods of treating a subject with a cancer comprising administering to the subject an effective amount of a compound represented by Structural Formula (I-0), (I) or (I)′ in combination with an effective anti-cancer therapy. In one embodiment, the cancer is a metastatic cancer. A “metastatic cancer” is a cancer that has spread from its primary site to other parts of the body.

In another embodiment, the present teachings are directed to a method of treating a subject with a drug-resistant cancer. A “drug-resistant cancer” is a cancer that is not responsive to one, two, three, four, five or more drugs that are typically used for the treatment of the cancer. In one embodiment, the drug-resistant cancer is mediated by the growth of tumor-initiating cells.

Suitable methods known in the art can be used for assessing a subject to determine whether the cancer is in remission. For example, the size of the tumor and/or tumor markers, usually proteins associated with tumors, can be monitored to determine the state of the cancer. Size of the tumor can be monitored with imaging devices, such as X-ray, MRI, CAT scans, ultrasound, mammography, PET and the like or via biopsy.

For methods described herein, e.g., coadministration methods, the anti-cancer therapy are selected from the group consisting of surgery, radiation therapy, immunotherapy, endocrine therapy, gene therapy and administration of an anti-cancer agent. Alternatively, the anti-cancer therapy is radiation therapy. In another alternative, the anti-cancer therapy is immunotherapy. In another alternative, the anti-cancer therapy is administration of an anti-cancer agent. In yet another alternative, the anti-cancer therapy is surgery.

Radiation therapy is the use of radiation to kill, destroy or treat the cancers. Exemplary radiation therapy includes, but is not limited to, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and radioisotope therapy (i.e., systemic radioactive isotopes therapy),

An endocrine therapy is a treatment that adds, blocks or removes hormones. For example, chemotherapeutic agents that can block the production or activity of estrogen have been used for treating breast cancer. In addition, hormonal stimulation of the immune system has been used to treat specific cancers, such as renal cell carcinoma and melanoma. In one embodiment, the endocrine therapy comprises administration of natural hormones, synthetic hormones or other synthetic molecules that may block or increase the production of the body's natural hormones. In another embodiment, the endocrine therapy includes removal of a gland that makes a certain hormone.

As use herein, a gene therapy is the insertion of genes into a subject's cell and biological tissues to treat diseases, such as cancer. Exemplary gene therapy includes, but is not limited to, a germ line gene therapy and a somatic gene therapy.

Immunotherapy (also called biological response modifier therapy, biologic therapy, biotherapy, immune therapy, or biological therapy) is treatment that uses parts of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells, or enhance a response against cancer cells. Immunotherapies include active and passive immunotherapies. Active immunotherapies stimulate the body's own immune system while passive immunotherapies generally use immune system components created outside of the body.

Examples of active immunotherapies include, but are not limited to vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or Tumor-Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2 (IL-2) or Lymphokine-Activated Killer (LAK) Cell Therapy.

Examples of passive immunotherapies include but are not limited to monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive material attached whereas conjugated monoclonal antibodies are joined to, for example, a chemotherapy drug (chemolabeled), a radioactive particle (radiolabeled), or a toxin (immunotoxin). Examples of these naked monoclonal antibody drugs include, but are not limited to Rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B cell non-Hodgkin lymphoma; Trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; Alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B cell chronic lymphocytic leukemia (B-CLL); Cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan to treat, for example, advanced colorectal cancer and head and neck cancers; and Bevacizumab (Avastin) which is an antiangiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of the conjugated monoclonal antibodies include, but are not limited to Radiolabeled antibody Ibritumomab tiuxetan (Zevalin) which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B cell non-Hodgkin lymphoma; radiolabeled antibody Tositumomab (Bexxar) which is used to treat, for example, certain types of non-Hodgkin lymphoma; and immunotoxin Gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML). BL22 is a conjugated monoclonal antibody for treating, for example, hairy cell leukemia, immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors, and radiolabeled antibodies such as OncoScint for example, for colorectal and ovarian cancers and ProstaScint for example, for prostate cancers.

Further examples of therapeutic antibodies that can be used include, but are not limited to, HERCEPTIN® (Trastuzumab) (Genentech, CA) which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO® (abciximab) (Centocor) which is an anti-glycoprotein IIb/IIIa receptor on the platelets for the prevention of clot formation; ZENAPAX® (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREX™ which is a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2 which is a murine anti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225 which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™ which is a humanized anti-αVβ3 integrin antibody (Applied Molecular Evolution/MedImmune); Campath 1H/LDP-03 which is a humanized anti CD52 IgG1 antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN™ which is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE™ which is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (Tc-99m-labeled; radioimaging; Immunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primatied anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN™ is a radiolabelled murine anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC/Scikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-α antibody (CAT/BASF); CDP870 is a humanized anti-TNF-α Fab fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgG1 antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-sreptdavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-α IgG4 antibody (Celltech); LDP-02 is a humanized anti-α4β7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN™ is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-152 is a human anti-TGF-β₂ antibody (Cambridge Ab Tech).

Immunotherapies that can be used in the present teachings include adjuvant immunotherapies. Examples include cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guérin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IFA); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of, interleukins, for example, IL-2 with other cytokines, such as IFN-alpha.

Alternatively, the anti-cancer therapy described herein includes administration of an anti-cancer agent. An “anti-cancer agent” is a compound, which when administered in an effective amount to a subject with cancer, can achieve, partially or substantially, one or more of the following: arresting the growth, reducing the extent of a cancer (e.g., reducing size of a tumor), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components) or increasing longevity of the subject.

The anti-cancer agent suitable for use in the methods described herein includes any anti-cancer agents that have been approved for the treatment of cancer. In one embodiment, the anti-cancer agent includes, but is not limited to, a targeted antibody, an angiogenesis inhibitor, an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a podophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplastic agent and other antineoplastic agents.

Examples of alkylating agents useful in the methods of the present teachings include but are not limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful in the methods of the present teachings include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of plant alkaloids and terpenoids or derivatives thereof include, but are not limited to, vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine), podophyllotoxin, and taxanes (e.g., paclitaxel, docetaxel). Examples of a topoisomerase inhibitor include, but are not limited to, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate and teniposide. Examples of antineoplastic agents include, but are not limited to, actinomycin, anthracyclines (e.g., doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin), bleomycin, plicamycin and mitomycin.

In one embodiment, the anti-cancer agents that can be used in the present teachings include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Yet other anti-cancer agents/drugs that can be used in the present teachings include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred additional anti-cancer drugs are 5-fluorouracil and leucovorin.

In one embodiment, the anti-cancer agents that can be used in methods described herein are selected from the group consisting of paclitaxel, docetaxel, 5-fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan and a combination thereof.

In one embodiment, the anti-cancer agent and the compound represented by Structural Formula (I-0), (I) or (I)′ are administered contemporaneously. When administered contemporaneously, the anti-cancer agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-cancer agent are administered separately. Alternatively, the compound and the additional anti-cancer agent can be administered sequentially, as separate compositions, within an appropriate time frame (e.g., a cancer treatment session/interval (e.g., about 1.5 to about 5 hours to about 10 hours to about 15 hours to about 20 hours; about 1 day to about 2 days to about 5 days to about 10 days to about 14 days)) as determined by the skilled clinician (e.g., a time sufficient to allow an overlap of the pharmaceutical effects of the therapies). The compound and the additional anti-cancer agent can be administered in a single dose or multiple doses in an order and on a schedule suitable to achieve a desired therapeutic effect (e.g., inhibition of tumor growth).

In one embodiment, the subject in the methods described herein has not been previously treated with a TTK inhibitor (e.g., the compound represented by Structural Formula (I-0), (I) or (I)′).

The term “inhibiting the growth of tumor-initiating cells” refers to decreasing the rate of the proliferation and/or survival of the tumor-initiating cells.

As used herein, the term “reducing the likelihood of recurrence of a cancer” means partially or totally inhibiting, delaying the return of a cancer at or near a primary site and/or at a secondary site after a period of remission. It also means that the cancer is less likely to return with treatment described herein than in its absence.

As used herein, the term “remission” refers to a state of cancer, wherein the clinical symptoms or indicators associated with a cancer have disappeared or cannot be detected, typically after the subject has been successfully treated with an anti-cancer therapy.

As used herein, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, reducing the likelihood of the spread of the disease, delay or slowing of disease progression, amelioration or palliation of the disease state, whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treatment” also includes reducing the likelihood of reoccurrence of the disease.

As used herein, “treating a subject with a cancer” includes achieving, partially or substantially, one or more of the following: arresting the growth, reducing the extent of the cancer (e.g., reducing size of a tumor), inhibiting the growth rate of the cancer, ameliorating or improving a clinical symptom or indicator associated with the cancer (such as tissue or serum components) or increasing longevity of the subject; and reducing the likelihood of recurrence of the cancer.

Generally, an effective amount of a compound taught herein varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. An effective amount of a compound of the present teachings may be readily determined by one of ordinary skill by routine methods known in the art.

The term an “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the cancer (e.g., as determined by clinical symptoms or the amount of cancer cells) in a subject as compared to a control.

In an embodiment, an effective amount of a compound taught herein ranges from about 0.1 to about 1000 mg/kg body weight, alternatively about 1 to about 500 mg/kg body weight, and in another alternative, from about 20 to about 300 mg/kg body weight. In another embodiment, an effective amount of a compound taught herein ranges from about 0.5 to about 5000 mg/m², alternatively about from 5 to about 2500 mg/m², and in another alternative from about 50 to about 1000 mg/m². The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject suffering from cancer or reduce the likelihood of recurrence of a cancer. These factors include, but are not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject and other diseases present.

Moreover, for methods described herein (including treating a subject with a cancer or reducing the likelihood of recurrence of a cancer), a “treatment” or dosing regimen of a subject with an effective amount of the compound of the present teachings may consist of a single administration, or alternatively comprise a series of applications. For example, the compound of the present teachings may be administered at least once a week. However, in another embodiment, the compound may be administered to the subject from about one time per week to once daily for a given treatment. The length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of the compounds of the present teachings, or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.

A “subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

The compounds taught herein can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the present teachings may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

The compounds taught herein can be suitably formulated into pharmaceutical compositions for administration to a subject. The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

Typically, for oral therapeutic administration, a compound of the present teachings may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Typically for parenteral administration, solutions of a compound of the present teachings can generally be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersion of, and sterile powders of, a compound described herein for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.

For nasal administration, the compounds of the present teachings can be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

For buccal or sublingual administration, the compounds of the present teachings can be formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.

For rectal administration, the compounds described herein can be formulated in the form of suppositories containing a conventional suppository base such as cocoa butter.

The compounds of invention may be prepared by methods known to those skilled in the art, as illustrated by the general schemes and procedures below and by the preparative examples that follow. All starting materials are either commercially available or prepared by methods known to those skilled in the art and the procedures described below.

In accordance with another aspect of the present invention, the compounds of the invention can be prepared by processes analogues to those established in the art. General methods to synthesize the claimed compounds are elaborated below in Example A.

EXEMPLIFICATION Example A: Synthesis General Methods

Commercially available starting materials, reagents, and solvents were used as received. In general, anhydrous reactions were performed under an inert atmosphere such as nitrogen or Argon. PoraPak® Rxn CX refers to a commercial cation-exchange resin available from Waters. Microwave reactions were performed with a Biotage Initiator microwave reactor. Reaction progress was generally monitored by TLC using Merck silica gel plates with visualization by UV at 254 nm, by analytical HPLC or by LCMS (Bruker Exquire 4000 or Waters Acquity UPLC system). Flash column chromatographic purification of intermediates or final products was performed using 230-400 mesh silica gel 60 from EMD chemicals or Silicycle, or purified using a Biotage Isolera with KP-SIL or HP-SIL silica cartridges, or KP-NH basic modified silica and corresponding samples. Reverse-phase HPLC purification was performed on a Varian PrepStar model SD-1 HPLC system with a Varian Monochrom 10 u C-18 reverse-phase column using a of about 5-30% MeCN or MeOH/0.05% TFA-H₂O to 70-90% MeCN or MeOH/0.05% TFA in H₂O over a 20-40-min period at a flow rate of 30-80 mL/min. Reverse phase purification was also performed using a Biotage Isolera equipped with a KP-C18-H column using a between 10-95% MeOH or CH₃CN/0.1% TFA in H₂O. Proton NMRs were recorded on a Bruker 400 MHz spectrometer, and mass spectra were obtained using a Bruker Esquire 4000 spectrometer or Waters Acquity UPLC system.

Compound names were generated using the software built into CambridgeSoft-PerkinElmer's ChemBioDraw Ultra version 11.0 or 12.0.

Abbreviations:

Ac Acetyl

aq aqueous

anh anhydrous

Ar argon

BINOL 1,1′-binaphthalene-2,2′-diol

Boc tert-butoxycarbonyl

br. broad

calcd calculated

d doublet (only when used within 1H NMR spectra)

d day

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-dichloroethane

DCC N,N′-dicyclohexylcarbodiimide

DCM dichloromethane

DEA diethylamine

de diastereomeric excess

DIPEA diisopropylethylamine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

dppf 1,1′-bis(diphenylphosphino) ferrocene

h hour

hal halogen

HPLC high performance liquid chromatography

IPA iso-propanol

LC-MS liquid chromatography coupled to mass spectrometry

min minute

m multiplet

mCPBA meta-chloroperoxybenzoic acid

MS ESI mass spectra, electrospray ionization

NMR nuclear magnetic resonance

NBS N-Bromosuccinimide

O/N overnight

pin pinacol

PMB para-methoxybenzyl

prep preparative

PTSA para-toluenesulfonic acid

RBF round bottomed flask

rt room temperature

Rt retention time

RP reverse phase

s singlet

satd saturated

SMs starting materials

S_(N)Ar Nucleophilic Aromatic Substitution

SPE solid phase extraction

t triplet

TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

TEA triethylamine

temp. temperature TFA trifluoroacetic acid

TLC thin layer chromatography

THF tetrahydrofuran

THP tetrahydropyranyl

xs excess

By way of illustration, pyrazolotriazine compounds of Structural Formula 6 may be prepared by the methods outlined in Scheme 1. Treatment of 8-halo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine 1 with suitably substituted aliphatic primary amine or alcohol in the presence of base such as DIPEA, TEA, pyridine and DBU yields the desired intermediate 2. In the case where primary amine is used in the previous step, protection of the nitrogen is performed using standard procedures well known in the art before the Suzuki-Miyaura cross coupling reaction. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Green, “Protecting Groups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc., 1999. The subsequent Suzuki-Miyaura cross coupling is carried out in the presence of a Pd catalyst (e.g. PdCl₂(dppf) or Pd(PPh₃)₄), and a suitably substituted aryl boronate ester or boronic acid and a base (e.g. aq K₃PO₄, or Na₂CO₃) at high temperatures (e.g. 100-130° C.). Removal of protecting group under acidic conditions (e.g. for PG=PMB at TFA, 35-80° C.) followed by oxidation of methylsulfide using oxidants (e.g. mCPBA) afforded the desired intermediate 5. The compounds of the invention 6 can be synthesized via an nucleophilic aromatic substitution in the presence of primary/secondary amines or alcohols/phenols in the presence of a suitable base (e.g. DIPEA, TEA, DBU, NaH), at a temperature in the range of rt to 80° C.

Alternatively, final compound 6 can be synthesized using the reaction sequence depicted in Scheme 2 where intermediate 4 undergoes an oxidation of methylsulfide followed by nucleophilic aromatic substitution and removal of protecting group using the reaction conditions described above.

The starting materials of formula I can be synthesized using procedures analogues to those well known in the arts of heterocyclic and organic chemistry for the production of structurally analogous compounds. Thus, intermediate 7 is synthesized according to a procedure from International Patent Application Publication No. WO2011/079231. Desired intermediate 1 can be obtained by bromination of intermediate 7 using NBS or other brominating reagents.

Compounds described herein can be prepared in a manner analogous to the general procedures described above or the detailed procedures described in the examples herein.

Pyrazolopyrimidine compounds of the present invention may be prepared by the methods outlined in Scheme 4.

General Method a (Amination)

To a cooled (0° C.) DCM solution (0.1-1 M) of 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1 equiv) or 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.0 equiv) was added primary amine (1-2 equiv) and DIPEA or TEA (1-2 equiv). Alternatively, primary amine (2-3 equiv) was added alone without DIPEA/TEA. The reaction was stirred at rt for 0.5-24 h. The product was partitioned between EtOAc or DCM and satd NaHCO₃ solution, dried over Na₂SO₄ or MgSO₄, filtered, and concentrated to dryness. In the majority of examples the crude product was used without further purification or alternatively the material was purified by flash chromatography.

General Method B (Boc Protection)

To a solution of pyrazolo[1,5-a]pyrimidin-7-amine derivative (1 equiv) in DCM was added Boc₂O (0.8-1.5 equiv), followed by DMAP (0.1-0.2 equiv) and Et₃N (1-2 equiv). The resulting mixture was stirred at rt and purified by flash chromatography (gradient: EtOAc/hex 0-100%).

General Method B2 (PMB Protection)

A solution of 8-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1 equiv) in DMF (0.2-1M), 4-methoxybenzyl chloride (1.0-1.2 equiv), and K₂CO₃ (2 equiv) was heated to 60° C. for 2-4 h. The product was partitioned between EtOAc and H₂O, dried over Na₂SO₄ or MgSO₄, filtered, concentrated to dryness, and purified by flash chromatography.

General Method C (Nucleophilic Substitutions of Amines)

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) or 2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 equiv) in THF, dioxane, DME, DMF or NMP was added amines or amine-HCl (1-2 equiv) and DIPEA (1-3 equiv). The resulting mixture was stirred at rt for 24 h or more generally the reaction was heated in a microwave reactor, an oil bath or a reaction block at temperatures from 35-130° C. for 2-12 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography.

Alternatively, a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) or 2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 equiv) and amine or aniline (2-22 equiv) was heated in a microwave reactor, an oil bath or a reaction block at temperatures from 35-170° C. for 2-12 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography.

General Method D (Nucleophilic Substitutions of Alcohols)

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) or 2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 equiv) and alcohol (1-3 equiv) in DMF or THF at 0° C. was added 60% NaH (1.5-6 equiv). The resulting mixture was stirred at rt for 1-4 h. After cooling to 0° C., quenching with satd NH₄Cl and H₂O, it was extracted with EtOAc and purified by flash chromatography.

General Method E (Nucleophilic Substitutions of Phenols or Hydroxylpyridine)

Using phenol and K₂CO₃:

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) and phenol (2-3 equiv) in DMF was added K₂CO₃ (3 equiv). The resulting mixture was stirred O/N at rt and quenched with H₂O. The precipitates were collected by suction filtration and dried to give the desired product. Alternatively, the aqueous layer was extracted with EtOAc. The organic layer was dried (Na₂SO₄ or MgSO₄), filtered, concentrated to dryness and purified by flash chromatography.

Using Phenol and DBU:

A mixture of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) or 2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 equiv) in DME or DMF, phenol (2-4 equiv), and DBU (2-4 equiv) was heated in a microwave reactor, an oil bath or a reaction block at temperatures 80-100° C. for 1-4 h. Solvent was removed and the crude product was purified by flash chromatography.

Using Phenoxide:

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) in DMF was added sodium phenoxides (1-1.5 equiv, commercial or freshly made using phenols and NaOH in H₂O). The resulting mixture was stirred at rt for 30 min to O/N and quenched with H₂O. The precipitates were collected by suction filtration and dried to give the desired product. Alternatively the aqueous layer was extracted with EtOAc. The organic layer was dried (Na₂SO₄ or MgSO₄), filtered, concentrated to dryness and purified by flash chromatography.

General Method F (Suzuki-Miyaura Coupling; Followed by Boc or PMB Deprotection if Applicable)

A mixture of pyrazolo[1,5-a]pyrimidin-3-bromine derivative (1.0 equiv) or 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 equiv), boronic acid or aryl boronate ester (1-3 equiv), aq K₃PO₄ (1-2 M, 3-5 equiv) and PdCl₂dppfDCM (0.05-0.2 equiv) in THF was heated under Ar in a microwave reactor, an oil bath or a reaction block at temperatures 80-130° C. for 2 h to 2 days. The product was partitioned between EtOAc and H₂O, dried over Na₂SO₄ or MgSO₄, filtered and concentrated to dryness, then purified by flash chromatography.

If Boc deprotection is required, the above compound was redissolved in DCM and treated with TFA and stirred O/N. After removal of TFA, it was triturated with MeOH or purified by flash chromatography or prep-HPLC.

Alternatively, the Boc deprotection can be done in microwave in mixture of H₂O and DMF or NMP or EtOH at 100-140° C. for 1-4 h and purified by prep-HPLC, reversed phase or normal phase Biotage column.

For PMB deprotection: A solution of N-(4-methoxybenzyl)-2-(methylthio)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1 equiv) in a mixture of DCM and TFA (2:1 v/v) or DCE and TFA (3:1 v/v) was heated in a microwave reactor, an oil bath or a reaction block at temperatures 60-100° C. for 30 min-30 h. Solvent was removed in vacuo and the crude product was purified by chromatography.

General Method G (Borylation of Aryl Halides): Using B₂pin₂/Pd

A mixture of aryliodide or arylbromide (1 equiv), B₂pin₂ (1.2 to 1.5 equiv), KOAc (3 equiv.) and DMF or DMSO was purged with Ar for 10 min. PdCl₂(dppf).DCM (3-5 mol %) was added, the vial sealed and heated at 80-100° C. for 2-6 h. The product was partitioned between EtOAc and satd aq NaHCO₃, washed with brine, dried over Na₂SO₄ or MgSO₄, filtered, and concentrated to dryness. The crude product was purified by flash chromatography to give the title compound.

General Method H (Substitution with Sodium Sulfinate)

A mixture of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) and sodium sulfinate (1-1.2 equiv) in DMF was heated at 60° C. in oil bath or microwave for 1-2 h. After removal of solvents, it was purified by flash chromatography on SiO₂.

General Method I (Suzuki on Pyrazolo[1,5-a]Pyrimidin-5-Phenylsulphonyl Derivative)

To a mixture of the pyrazolo[1,5-a]pyrimidin-5-phenylsulphonyl derivative (1 equiv) and N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1-1.5 equiv) in THF was added 2 M K₃PO₄ (3 equiv), followed by PdCl₂dppfDCM (2-10 mol %). The resulting mixture was purged with Ar and then heated at 60° C. for 1.5 h to O/N. It was diluted with brine, extracted with EtOAc and combined. After removal of solvents, the residue was purified by flash chromatography on SiO₂.

General Method J (Nucleophilic Substitutions on Benzenesulfonate, Followed by Boc Deprotection)

To a solution of pyrazolo[1,5-a]pyrimidin-5-phenylsulphonyl derivative (1 equiv, 0.05-0.3 M) in DMF or NMP was added amines, amine-HCls (1-3 equiv) and DIPEA (1-3 equiv) or phenolates (prepared from NaOH and phenols in H2O, after drying). The resulting mixture was heated in microwave at 100-130° C. for 1-6 h.

For the Boc deprotection, after adding 0.5-2 volumes of H₂O, the resulting mixture was heated in microwave at 120-140° C. for 1-4 h and purified by prep-HPLC or reversed phase Biotage column.

Intermediates: Synthesis of 4-bromo-N-cyclopropyl-2-methylbenzamide

To a suspension of 4-bromo-2-methylbenzoic acid (43.0 g, 200 mmol) and oxalyl dichloride (30.5 g, 240 mmol) in DCM (300 mL) was added DMF (0.1 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction turned into a clear yellow solution slowly over 16 h. Solvent was then removed in vacuo, and the crude product was used in the next step without further purification. The crude product was redissolved in DCM (300 mL) and cooled to 0° C. A mixture of TEA (42 mL, 300 mmol) and cyclopropylamine (12.6 g, 220 mmol) in DCM (100 mL) was added slowly over 15 min, and the resulting mixture was stirred at rt for 2 h. The reaction was diluted with DCM (200 mL) and water was added. The resulting mixture was extracted with DCM and the combined organic extracts were dried over MgSO₄ and concentrated to give the desired product as a pale pink solid (50.1 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.37 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 5.93 (br, s, 1H), 2.90-2.85 (m, 1H), 2.40 (s, 3H), 0.90-0.85 (m, 2H), 0.62-0.58 (m, 2H); MS ESI [M+H]⁺ 253.9, calcd for [C₁₁H₁₂BrNO+H]⁺ 254.0.

Synthesis of N-(4-bromo-2-methylphenyl)cyclopropanecarboxamide

In a 100 mL RBF, 4-bromo-2-methylaniline (3.7 g, 20 mmol) and DIPEA (6.95 mL, 40 mmol) were combined with DMF (40 mL). The reaction was cooled to 0° C. in an ice bath and cyclopropanecarbonyl chloride (2.1 g, 20 mmol) was added. The mixture was stirred at 0° C. for 1 h. Water and EtOAc were added to separate the phases and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound as a white solid (4.76 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85-7.72 (m, 1H), 7.38-7.28 (m, 2H), 7.15-7.02 (m, 1H), 2.27 (s, 3H), 1.57-1.48 (m, 1H), 1.10 (quint, J=3.9 Hz, 2H), 0.92-0.79 (m, 2H); MS ESI [M+H]⁺ 253.9, calcd for [C₁₁H₁₂BrNO+H]⁺ 254.0.

Synthesis of N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a mixture of 4-bromo-N-cyclopropyl-2-methylbenzamide (3.73 g, 14 mmol), Bis(pinacolato)diboron (5.59 g, 22 mmol), anh KOAc (4.29 g, 43 mmol) in DMF (37 mL) was purged with Ar for 10 min at rt. Then PdCl₂(dppf).DCM (0.59 g, 5 mol %) was added and the reaction was heated at 100° C. in oil bath for 4 h. After reaction completion the reaction mass was diluted with EtOAc (200 mL) & H₂O (100 mL). The combined layer filtered through celite pad and washed it with little EtOAc. The aq. layer further extracted with EtOAc (50 mL) and the combined organic layer washed with brine, dried over Na₂SO₄, filtered, and concentrated to give crude oily residue. The crude product was purified by flash chromatography (gradient: EtOAc/hex 0-100%) to give the title compound as a creamy solid (4.15 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.66 (s, 1H), 7.63-7.61 (d, J=7.6 Hz, 1H), 7.32-7.30 (d, J=7.6 Hz, 1H), 5.85 (s, 1H), 2.93-2.87 (m, 1H), 2.46 (s, 3H), 1.35 (s, 12H), 0.90-0.86 (m, 2H), 0.63-0.59 (m, 2H); MS ESI [M+H]⁺ 302.2, calcd for [C₁₇H₂₄BNO₃+H]⁺ 302.2.

The following compounds were synthesized according to the synthesis of General Method G

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]+ Salt form N-(2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl) cyclopropanecarboxamide

[C₁₇H₂₄BNO₃ + H]⁺ 302.2; 302.4 1.13 g (63%); white solid; free base SMs: N-(4-bromo-2-methylphenyl)cyclopropanecarboxamide (1.5 g, 5.9 mmol), (PinB)₂ (2.3 g, 8.9 mmol), PdCl₂dppf DCM (242 mg, 0.30 mmol). ¹H NMR (400 MHz, CDCl3) δ ppm 8.03 (br, s, 1H), 7.70-7.60 (m, 2H), 7.36-7.29 (m, 1H), 2.31 (s, 3 H), 1.58-1.48 (m, 1H), 1.34 (s, 12 H), 1.15-1.05 (m, 2H), 0.90-0.80 (m, 2H).

Synthesis of (cis)-4-hydroxy-N-(4-methoxybenzyl)cyclohexanecarboxamide

TBTU (3.21 g, 10.0 mmol) was added in one portion to a stirred DMF (anh., 20 mL) solution of (cis)-4-hydroxycyclohexanecarboxylic acid (1.44 g, 9.9 mmol), 4-methoxybenzylamine (1.37 g, 9.9 mmol) and DIPEA (1.8 mL, 10.3 mmol) at rt. Stirring was continued for 21 h, then the reaction was diluted with H₂O and taken into EtOAc (150 mL). The organic phase was washed with H₂O (50 mL and 30 mL). The aq. phases were combined, concentrated under reduced pressure and purified by RP HPLC (C18, MeOH—H₂O) to afford the title compound as a white solid (0.83 g, 32%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.21 (d, J=8.28 Hz, 2H), 6.88 (d, J=8.28 Hz, 2H), 5.69 (br. s., 1H), 4.39 (d, J=5.52 Hz, 2H), 4.01 (br. s., 1H), 3.81 (s, 3H), 2.12-2.26 (m, 1H), 1.78-1.97 (m, 4H), 1.76-1.66 (m, 2H), 1.65-1.57 (m, 2H); MS ESI [M+H]⁺ 264.2, calcd for [C₁₅H₂₁NO₃+H]⁺ 264.15.

Synthesis of (cis)-4-(((4-methoxybenzyl)amino)methyl)cyclohexanol

LiAlH₄ (1.0 M in THF, 10.0 mL, 10 mmol) was added slowly to an anh THF (40 mL) solution of (cis)-4-hydroxy-N-(4-methoxybenzyl) cyclohexanecarboxamide (0.83 g, 3.1 mmol) at 0° C. Stirring was continued with cooling for another 5 min, later the reaction was allowed to warm to rt and subsequently heated at 60° C. overnight. The reaction was cooled to rt and poured carefully to a stirred cold (0° C.) mixture of xs Na₂SO₄.10H₂O in DCM. The reaction was stirred for additional 2 h at rt and then filtered under vacuum. The solid was rinsed with DCM and the filtrate was concentrated under reduced pressure to give the desired material that was used without further purification (pale yellow oil, 0.79 g, quant). MS ESI [M+H]⁺ 250.3, calcd for [C₁₅H₂₃NO₂+H]⁺ 250.18.

Synthesis of 8-bromo-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine

The title compound was synthesized according to General Method A utilizing 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.5 g, 5.4 mmol), 4-(aminomethyl)tetrahydro-2H-pyran hydrochloride (0.81 g, 534 mmol), and DIPEA (1.9 mL, 11 mmol) at 0° C.-rt for 1 h. The desired product was isolated as a beige solid (1.8 g, 95%) and was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (s, 1H), 6.53 (br s, 1H), 4.01 (dd, J=11.3, 3.6 Hz, 2H), 3.58 (t, J=6.6 Hz, 2H), 3.41 (t, J=11.8 Hz, 2H), 2.61 (s, 3H), 1.94-2.00 (m, 1H), 1.68-1.73 (m, 2H), 1.38-1.49 (m, 2H); MS ESI [M+H]⁺ 358.2, calcd for [C₁₂H₆BrN₅OS+H]⁺ 358.03.

Synthesis of (1r,4r)-4-(((4-methoxybenzyl)amino)methylcyclohexanol

A sealed vial charged with (1r,4r)-4-hydroxycyclohexanecarboxylic acid (0.505 g, 3.20 mmol), (4-methoxyphenyl)methanamine (0.460 g, 3.35 mmol), 1H-1,2,4-triazole (44 mg, 0.2 mmol), DBU (0.100 g. 0.66 mmol) was heated with stirring at 70° C. for 3 d. The reaction was directly loaded a SiO₂ column and purified by flash chromatography (gradient: EtOAc/hex 0-30%) to afford (1r,4r)-4-hydroxy-N-(4-methoxybenzyl)-cyclohexanecarboxamide (705 mg, 84%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.19 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.28 (s, 2H), 3.77 (s, 3H), 3.57-3.46 (m, 1H), 2.20-2.09 (m, 1H), 2.05-1.94 (m, 2H), 1.90-1.80 (m, 2H), 1.62-1.49 (m, 2H), 1.33-1.19 (m, 2H); MS ESI [M+H]⁺ 264.2, calcd for [C₁₂H₂₁NO₃+H]⁺ 264.1.

A solution of the above (1r,4r)-4-hydroxy-N-(4-methoxybenzyl)cyclohexanecarboxamide (0.705 g, 2.7 mmol) in anh THF (30 mL) was treated with LiAlH₄ (1 M in THF, 8 mL, 8 mmol) at rt and then heated at reflux O/N under Ar. The reaction mixture was cooled to rt and added slowly to a stirred suspension of xs Na₂SO₄*10H₂O in DCM at 0° C. The reaction was stirred for 2 h then filtered and concentrated to provide the title compound (0.67 g, quantitative) as pale orange gum used without further purification. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.25 (d, J=8.53 Hz, 2H), 6.92-6.85 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 3.68 (s, 2H), 3.61-3.54 (m, 1H), 3.51-3.40 (m, 1H), 2.40 (d, J=6.8 Hz, 2H), 1.99-1.90 (m, 2H), 1.88-1.74 (m, 2H), 1.63-1.58 (m, 1H), 1.52-1.41 (m, 1H), 1.35-1.15 (m, 2H), 1.08-0.85 (m, 2H); MS ESI [M+H]⁺ 250.2, calcd for [C₁₂H₂₃NO₂+H]⁺ 250.2.

Synthesis of 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine

To a stirred solution of sodium ethoxide in EtOH, which was prepared from sodium (281.3 g, 12.0 mol) and EtOH (10 L) by the conventional method, were added diethyl malonate (963.7 g, 6.02 mol) at ambient temperature and then compound 1H-pyrazol-3-amine (500 g, 6.02 mol). The reaction mixture was refluxed for 12 hours. After cooled to room temperature, the precipitates were collected by filtration and dissolved in water. The aqueous solution was acidified with 2 M HCl (pH=2). The resulting precipitates were collected by filtration and dried under reduced pressure to afford pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (649 g, 71%) as a yellow solid, which was used for the next reaction without further purification.

A stirred suspension of pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (265 g, 1.75 mol) and N,N-dimethylaniline (335.6 mL) in POCl₃ (2.00 kg, 13.2 mol) was refluxed for 4 hours. After cooled to room temperature, the reaction mixture was poured into ice-water, and stirred for 30 min, neutralized with saturated aqueous sodium carbonate and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO₄, filtered and evaporated. The residue was purified by column chromatography on silica gel (gradient: EtOAc/PE 1:10) to give 5,7-dichloropyrazolo[1,5-a]pyrimidine (287 g, 87%) as a yellow solid.

To a solution 5,7-dichloropyrazolo[1,5-a]pyrimidine (246.6 g, 1.31 mol) in CH₃CN (1.8 L) was added NBS (245 g, 1.38 mol). The resulting mixture was stirred at room temperature for 2 hours. After removal of the solution, the reaction mixture was purified by column chromatography on silica gel (gradient: EtOAc/PE 1:5) to give the title compound (313.5 g, 89%) as light yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 7.04 (s, 1H), 8.21 (s, 1H); MS ESI [M+H]⁺ 265.9, calcd for [C₆H₂BrCl₂N₃+H]⁺ 265.9.

Synthesis of 3-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

To a solution of 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (2.67 g, 10 mmol) in DCM (30 mL) at 0° C. was added (tetrahydro-2H-pyran-4-yl)methan-amine (1.27 g, 11 mmol), followed by DIPEA (2.1 mL, 12 mmol). The resulting mixture was stirred at rt for h and purified by flash chromatography (gradient: EtOAc/hex 0-90%) to give the title compound as white solid (3.46 g, quantitative yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 6.55-6.43 (m, 1H), 6.00 (s, 1H), 4.08-4.00 (m, 2H), 3.43 (dt, J=12.0, 1.7 Hz, 2H), 3.32 (t, J=6.6 Hz, 2H), 2.06-1.94 (m, 1H), 1.78-1.71 (m, 2H), 1.51-1.38 (m, 2H); MS ESI [M+H]⁺ 345.1, calcd for [C₁₂H₁₄BrCN₄O+H]⁺ 344.9.

The following intermediates were synthesized according to General Method A:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form 8-bromo-2-(methylthio)-N-(2- morpholinoethyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine

[C₁₂H₁₇BrN₆ OS + H]⁺ 373.0; 372.8 1.108 g (88%); white solid; free base SMs: 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (945 mmol, 3.37 mmol), 2- morpholinoethanamine (0.47 ml, 3.61 mmol). ¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.05 (s, 1H), 3.85-3.65 (m, 6H), 2.75-2.55 (m, 9H). 8-bromo-2-(methylthio)-N-(3- morpholinopropyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine

[C₁₃H₁₉BrN₆ OS + H]⁺ 387.1; 387.1 3.47 g (100%); white solid; free base SMs: 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (2.5 g, 8..94 mmol), 3- morpholinopropan-1-amine (1.31 mL, 8.94 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.11 (br. s., 1 H), 7.85 (d, J = 0.8 Hz, 1 H), 3.90 (t, J = 4.5 Hz, 4 H), 3.72-3.80 (m, 2 H), 2.58-2.66 (m, 5 H), 2.54 (br. s., 4 H), 1.80-1.91 (m, 2 H). (cis)-4-(((8-bromo-2-(methylthio) pyrazolo[1,5-a][1,3,5]triazin-4-yl)(4- methoxybenzyl)amino)methyl) cyclohexanol

[C₂₁H₂₆BrN₅ O₂S + H]⁺ 492.1; 492.1 0.39 g (64%); white foam; free base SMs: 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (0.343 g, 1.23 mmol), (cis)-4- (((4-methoxybenzyl)amino)methyl)cyclohexanol (0.31 g, 1.24 mmol), DIPEA (0.22 mL, 1.24 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (s, 1 H), 7.18 (d, J = 8.28 Hz, 2 H), 6.85 (d, J = 8.53 Hz, 2 H), 5.01-5.62 (br.s. 2H), 4.01 (br. s., 1 H), 3.65-3.98 (br.s, 2H), 3.80 (s, 3 H), 2.57 (s, 3 H), 1.85-1.99 (m, 1 H), 1.69-1.80 (m, 2 H), 1.42-1.67 (m, 6 H). 3-bromo-5-chloro-N-(2- methoxyethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₉H₁₀BrClN₄O + H]⁺ 305.0; 304.9 2.94 (96%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (2.67 g, 10 mmol), 2-methoxyethanamine (1.9 mL, 21 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 6.70 (br, s, 1H), 6.02 (s, 1H), 3.69 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.2 Hz, 2H), 3.44 (s, 3H). 3-bromo-5-chloro-N-(2- morpholinoethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₂H₁₅BrCl N₅O + H]⁺ 360.0; 359.9 3.21 g (89%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (2.67 g, 10 mmol), 2-morpholinoethanamine (1.45 mL, 11 mmol), DIPEA (2.1 mL, 12 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.02-7.08 (m, 1H), 5.97 (s, 1H), 3.77 (t, J = 4.6 Hz, 2H), 3.47-3.42 (m, 4H), 2.77 (t, J = 5.8 Hz, 2H), 2.55 (t, J = 4.2 Hz, 4H). 3-bromo-5-chloro-N-(3- morpholinopropyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₃H₁₇BrCl N₅O + H]⁺ 376.0; 376.0 530 mg (75%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 1.873 mmol), 3-morpholinopropan- 1-amine (540 mg, 3.745 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.97 (br, s, 1H), 7.97 (s, 1H), 5.93 (s, 1H), 3.92 (t, J = 4.6 Hz, 4H), 3.56-3.40 (m, 2H), 2.69-2.61 (m, 2H), 2.55 (br, s, 4H), 2.00-1.87 (m, 2H). 3-bromo-5-chloro-N-(2-(tetrahydro- 2H-pyran-4-yl)ethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₃H₁₆BrCl N₄O + H]⁺ 361.0; 361.1 662 mg (98%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 1.873 mmol), 2-(tetrahydro-2H- pyran-4-yl)ethanamine (266 mg, 2.06 mmol), DIPEA (0.37 mL, 2.25 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 6.34 (br, s, 1H), 5.99 (s, 1H), 4.00 (dd, J = 11.2, 4.4 Hz, 2H), 3.52-3.34 (m, 4H), 1.77-1.63 (m, 5H), 1.48-1.33 (m, 2H). 3-bromo-5-chloro-N- isobutylpyrazolo[1,5-a]pyrimidin-7- amine

[C₁₀H₁₂BrCl N₄ + H]⁺ 303.0; 303.0 1.10 g (96%); clear oil; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1 g, 3.8 mmol), isobutylamine (304 mg, 4.2 mmol), DIPEA (1.44 mL, 8.34 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 6.47 (br, s, 1H), 5.99 (s, 1H), 3.26-3.16 (m, 2H), 2.12-1.98 (m, 1H), 1.07 (d, J = 6.5 Hz 6H). 1-((3-bromo-5-chloropyrazolo[1,5- a]pyrimidin-7-yl)amino)-2- methylpropan-2-ol

[C₁₀H₁₂BrCl N₄O + H]⁺ 319.0; 319.0 910 mg (76%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1 g, 3.8 mmol), 1-amino-2-methylpropan-2-ol (371 mg, 4.2 mmol), DIPEA (1.3 mL, 7.56 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1 H), 6.80 (br, s, 1H), 6.04 (s, 1H), 3.36 (d, J = 6.0 Hz, 2H), 1.61 (s, 1H), 1.39 (s, 6H). (1r,4r)-4-(((3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(4- methoxybenzyl)amin)methyl) cyclohexanol

[C₂₁H₂₄BrCl N₄O₂ + H]⁺ 479.1/481.1; 479.0/481.0 0.36 g (84%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (239 g, 0.89 mmol), (1r,4r)-4-(((4- methoxybenzyl)amino)methyl)cyclohexanol (223 mg, 0.89 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.01 (s, 1H), 7.12 (d, J = 8.28 Hz, 2H), 6.86 (d, J = 8.53 Hz, 2 H), 6.02 (s, 1H), 5.05 (s, 2H), 3.80 (s, 3H), 3.59 (d, J = 6.78 Hz, 2H), 3.57-3.46 (m, 1H, 2.02-1.91 (m, 2H), 1.84-1.70 (m, 2H),1.37 (d, J = 4.52 Hz, 1H), 1.31-1.15 (m, 2H), 1.05-0.90 (m, 2H). 3-bromo-5-chloro-N- (cyclopropylmethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₀H₁₀BrCl N₄ + H]⁺ 301.0; 301.0 5.3 g (92%); yellow solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.0 g, 19 mmol), cyclopropylmethanamine (1.5 g, 21 mmol), and DIPEA (6.6 mL, 38 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 6.50 (br. s, 1H), 5.97 (s, 1H), 3.25 (dd, J = 7.3, 5.5 Hz, 2H), 1.26-1.13 (m, 1H), 0.74-0.65 (m, 2H), 0.37 (q, J = 5.0 Hz, 2H). (1s,3s)-3-(((3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)amino)methyl)-1- methylcyclobutanol

[C₁₂H₁₄BrCl N₄O + H]⁺ 345.0; 345.1 6.1 g (94%); yellow solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.0 g, 19 mmol), cis-hydroxy-3- methylcyclobutane-1-methylamine (2.4 g, 21 mmol), and DIPEA (6.6 mL, 38 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 6.60-6.49 (m, 1H), 5.99 (s, 1H), 3.47 (t, J = 6.0 Hz, 2H), 2.38-2.27 (m, 3H), 1.96-1.85 (m, 2H), 1.43 (s, 3H). tert-butyl 4-(((3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)amino)methyl)-4- fluoropiperidine-1-carboxylate

[C₁₇H₂₂BrClFN₂ O₂ + H]⁺ 462.1; 462.1 6.0 g (100%); yellow solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (3.45 g, 12.9 mmol), tert-butyl 4- (aminomethyl)-4-fluoropiperidine-1-carboxylate (3.0 g, 12.9 mmol), and DIPEA (4.5 mL, 25.8 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.00 (s, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.19-3.93 (m, 2H), 3.58 (d, J = 6.5 Hz, 1H), 3.53 (d, J = 6.5 Hz, 1H), 3.10 (br. s., 2H), 2.04-1.90 (m, 2H), 1.77-1.62 (m, 2H), 1.48 (s, 9H). (R)-3-bromo-5-chloro-N- ((tetrahydrofuran-3- yl)methyl)pyrazolo[1,5-a]pyrimidin- 7-amine

[C₁₁H₁₂BrClN₄ O + H]⁺ 331.0; 330.9 13.6 g (91.3%); light yellow solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (12 g, 45 mmol), (R)-(tetrahydrofuran-3- yl)methanamine (5 g, 49.5 mmol), DIPEA (8.9 mL, 54 mmol), DCM (150 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 6.57 (br. s., 1 H), 6.02 (s, 1H), 4.01 (td, J = 8.4, 5.3 Hz, 1 H), 3.87 (dd, J = 9.2, 6.7 Hz, 1H), 3.84-3.77 (m, 1H), 3.73 (dd, J = 9.0, 4.3 Hz, 1H), 3.44-3.39 (m, 2H), 2.77-2.65 (m, 1H), 2.29-2.15 (m, 1H), 1.80-1.69 (m, 1H). (S)-3-bromo-5-chloro-N- ((tetrahydrofuran-3- yl)methyl)pyrazolo[1,5-a]pyrimidin- 7-amine

[C₁₁H₁₂BrClN₄ O + H]⁺ 331.0; 331.1 8.05 g (92.5%); light yellow solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (7 g, 26 mmol) (S)-(tetrahydrofuran-3- yl)methanamine (2.92 g, 28 mmol), DIPEA (5.71 mL, 32 mmol), DCM (56 mL). ¹H NMR identical to (R)-isomer 3-bromo-5-chloro-N-((1- methylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyrimidin- 7-amine

[C₁₃H₁₇BrCl N₅ + H]⁺ 358.0; 358.0 0.534 g, (78%); pale yellow foam; free base SMs: (1-methylpiperidin-4-yl)methanamine (0.247 g, 1.9 mmol), 3-bromo-5,7-dichloropyrazolo[1,5- a]pyrimidine (0.516 g, 1.9 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.91 (s, 1H), 6.58 (t, J = 5.9 Hz, 1H), 5.95 (s, 1H), 3.30 (t, J = 6.40 Hz, 2H), 2.99 (d, J = 11.8 Hz, 2H), 2.35 (s, 3H), 2.08 (td, J = 11.9, 2.0 Hz, 2H), 1.86-1.79 (m, 2H), 1.79-1.67 (m, 1H), 1.58-1.47 (m, 2H) 3-bromo-5-chloro-N-(2-(4- fluoropiperidin-1- yl)ethyl)pyrazolo[1,5-a]pyrimidin-7- amine

[C₁₃H₁₆BrClF N₅ + H]⁺ 376.0; 376.1 0.79 g, (68%); pale solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (0.92 g, 3.4 mmol), 2-(4-fluoropiperidin-1- yl)ethanamine (0.46 g, 3.1 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.08 (br. s., 1H), 5.97 (s, 1H), 5.05-4.52 (m, 1H), 3.47-3.36 (m, 2H), 2.82-2.72 (m, 2H), 2.72-2.58 (m, 2H), 2.57-2.43 (m, 2H), 2.05-1.86 (m, 4H)

Synthesis of 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine

The title compound was synthesized according to General Method B2 utilizing 8-bromo-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5] triazin-4-amine (1.8 g, 5.1 mmol), 4-methoxybenzyl chloride (0.83 mL, 6.1 mmol), K₂CO₃ (1.4 g, 10.1 mmol) and DMF (14 mL) at 60° C. for 4 h. The crude product was purified by flash chromatography (SiO₂, 0-50% EtOAc/DCM) to give the desired product as a white solid (2.2 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (s, 1H), 7.20 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.31 (br. s., 2H), 3.96 (dd, J=11.7, 2.9 Hz, 3H), 3.73-3.86 (m, 3H), 3.25-3.41 (m, 2H), 2.57 (s, 3H), 2.01-2.20 (m, 1H), 1.57-1.61 (m, 3H), 1.32-1.47 (m, 2H); MS ESI [M+H]⁺ 480.3, calcd for [C₂₀H₂₄BrN₅O₂S+H]⁺ 480.08.

Synthesis of tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of 3-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo [1,5-a]pyrimidin-7-amine (3.46 g, 10 mmol) in DCM (40 mL) was added Boc₂O (1.91 g, 8.8 mmol), followed by Et₃N (1.7 mL, 12 mmol) and DMAP (122 mg, 1 mmol). The resulting mixture was stirred at rt for 2 h. Additional Boc₂O (348 mg, 1.6 mmol) and Et₃N (0.28 mL, 2 mmol) were added and the mixture was stirred at rt for 1 h. After removal of solvents, it was purified by flash chromatography (gradient: EtOAc/hex 0-50%) to give the title compound as pale yellow foam (4.51 g, quantitative) after drying. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.75 (s, 1H), 3.96-3.86 (m, 2H), 3.71 (d, J=6.8 Hz, 2H), 3.29 (t, J=11.4 Hz, 2H), 1.85-1.73 (m, 1H), 1.67-1.58 (m, 2H), 1.45-1.25 (m, 11H; s, 9H at 1.34); MS ESI [M+H]⁺ 445.0, calcd for [C₁₇H₂₂BrClN₄O₃+H]⁺ 445.1.

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form 8-bromo-N-(4-methoxy benzyl)-2- (methylthio)-N-(2-morpholinoethyl) pyrazolo[1,5-a][1,3,5]triazin-4- amine

[C₂₀H₂₅BrN₆ O₂S + H]⁺ 493.1; 493.7 1.10 g (75%); colorless oil; free base SMs: 8-bromo-2-(methylthio)-N-(2-morpholinoethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.010 g, 3 mmol), 4-methoxybenzyl chloride (0.5 ml, 3.6 mmol). ¹H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.35-5.10 (m, 2H), 4.10-3.90 (m, 2H), 3.69 (s, 3H), 3.47-3.35 (m, 7H), 2.54 (t, J = 6.4 Hz, 2H), 2.37- 2.26 (m, 4H). 8-bromo-N-(4-methoxybenzyl)-2- (methylthio)-N-(3- morpholinopropyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine

[C₂₁H₂₇BrN₆ O₂S + H]⁺ 507.1; 507.8 3.25 g (84%); white solid; free base SMs: 8-bromo-2-(methylthio)-N-(3-morpholinopropyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (2.95 g, 7.64 mmol), 4-methoxybenzyl chloride (1.27 mL, 9.17 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (s, 1 H), 7.25 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 5.06-5.47 (br, s, 2 H), 3.98 (br. s., 2 H), 3.81 (s, 3 H), 3.70 (d, J = 4.3 Hz, 4 H), 2.57 (s, 3 H), 2.31- 2.45 (m, 6 H), 1.83-1.94 (m, 2 H).

The following intermediates were synthesized according to General Method B2:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin- 7-yl)(2-methoxyethyl)carbamate

[C₁₄H₁₈BrCl N₄O₃ + H]⁺ 405.0; 404.9 4.98 g (90%); light yellow solid; free base SMs: 3-bromo-5-chloro-N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.19 g, 13.7 mmol) Boc₂O (2.89 g, 13.3 mmol), DMAP (171 mg, 1.4 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.95 (s, 1H), 3.96 (t, J = 5.0 Hz, 2H), 3.59 (t, J = 5.0 Hz, 2H), 3.22 (s, 3H), 1.37 (s, 9H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(2-morpholinoethyl)carbamate

[C₁₇H₂₃BrCl N₅O₃ + H]⁺ 460.0; 460.8 3.59 g (88%); off white solid; free base SMS: 3-bromo-5-chloro-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.21 g, 8.9 mmol), Boc₂O (1.91 g, 8.8 mmol), DMAP (110 mg, 0.9 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (s, 1H), 6.90 (s, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.30-3.22 (m, 4H), 2.54 (t, J = 5.6 Hz, 2H), 2.24 (t, J = 4.4 Hz, 4H), 1.36 (s, 9H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(3-morpholinopropyl)carbamate

[C₁₈H₂₅BrCl N₅O₃ + H]⁺ 474.1; 474.9 626 mg (94%); pale yellow solid; free base SMs: 3-bromo-5-chloro-N-(3-morpholinopropyl)pyrazolo[1,5-a]pyrimidin-7-amine (530 mg, 1.41 mmol). Boc₂O (368 mg, 2.11 mmol), DMAP (17 mg, 0.14 mmol), Et₃N (0.24 mL, 1.69 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 7.27 (s, 1H), 6.83 (s, 1H), 3.88 (t, J = 7.3 Hz, 2H), 3.59 (t, J = 4.4 Hz, 4H), 2.34 (t, J = 6.9 Hz, 2H), 2.30-2.24 (m, 3H), 1.81 (quint, J = 7.2 Hz, 2H), 1.38 (s, 9H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(3-morpholinopropyl)carbamate

[C₁₈H₂₄BrCl N₄O₃ + H]⁺ 459.0; 459.3 800 mg (95%); yellow solid; free base SMS: 3-bromo-5-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine (662 mg, 1.83 mmol), Boc₂O (480 mg, 2.21mmol), DMAP (22 mg, 0.18 mmol), Et₃N (0.3 mL, 2.2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 6.76 (s, 1H), 3.93 (dd, J = 11.2, 3.6 Hz, 2H), 3.88- 3.81 (m, 2 H), 3.34 (t, J = 11.0 Hz, 2H), 1.62-1.47 (m, 5H), 1.38 (s, 9H), 1.34-1.21 (m, 2H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(isobutyl)carbamate

[C₁₅H₂₀BrCl N₄O₂ + H]⁺ 403.0; 403.0 1.19 g (81%); white solid; free base SMs: 3-bromo-5-chloro-N-isobutylpyrazolo[1,5-a]pyrimidin-7-amine (1.10 g, 3.64 mmol), Boc₂O (869 mg, 4.01 mmol), DMAP (44 mg, 0.36 mmol), TEA (0.61 mL, 4.37 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1 H), 6.76 (s, 1H), 3.65 (d, J = 7.3 Hz, 2H), 1.87-1.75 (m, 1H), 1.36 (s, 9H), 0.91 (d, J = 6.8 Hz, 6H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin- 7-yl)(2-((tert- butoxycarbonyl)oxy)-2- methylpropyl)carbamate

[C₂₀H₂₈BrCl N₄O₅ + H]⁺ 519.0; 519.0 809 mg (67%); white solid; free base SMs: 1-((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-methylpropan-2-ol (744 mg, 2.34 mmol), Boc₂O (869 mg, 4.01 mmol), DMAP (44 mg, 0.36 mmol), TEA (0.65 mL, 4.67 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.83 (s, 1H), 4.06 (s, 2H), 1.56 (s, 6H), 1.33 (s, 9H), 1.22 (s, 9H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(cyclopropylmethyl)carbamate

[C₁₅H₁₈BrCl N₄O₂ − C₄H₈]⁺ 345.0; 345.0 6.24 g (89%); yellow solid; free base SMs: 3-bromo-5-chloro-N-(cyclopropylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (5.25 g, 17.5 mmol), Boc₂O (5.70 g, 26.2 mmol), DMAP (0.21 g, 1.75 mmol), and TEA (7.3 mL, 52.5 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 6.85 (s, 1H), 3.72 (d, J = 7.3 Hz, 2H), 1.39 (s, 9H), 1.05-0.94 (m, 1H), 0.46-0.37 (m, 2 H) 0.13-0.03 (m, 2 H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3- methylcyclobutyl)methyl)carbamate

[C₂₂H₃₀BrCl N₄O₅ + H]⁺ 545.1; 545.1 0.90 g (40%); white solid; free base SMS: (1s,3s)-3-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-1- methylcyclobutanol (1.44 g, 4.2 mmol), Boc₂O (2.2 g, 10.5 mmol), DMAP (0.10 g, 0.84 mmol), and TEA (1.75 mL, 12.6 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.74 (s, 1H), 3.88 (d, J = 6.5 Hz, 2H), 2.17 (s, 3H), 1.99-1.88 (m, 2H), 1.47 (s, 3H), 1.45 (s, 9H), 1.35 (s, 9H). tert-butyl 4-(((3-bromo-5- chloropyrazolo[1,5-a]pyrimidin- 7-yl)(tert- butoxycarbonyl)amino)methyl)-4- fluoropiperidine-1-carboxylate

[C₂₂H₃₀BrClF N₅O₄ + H]⁺ 508.1; 508.1 7.0 g (97%); yellow solid; free base SMs: tert-butyl 4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-4- fluoropiperidine-1-carboxylate (6.0 g, 12.9 mmol), Boc₂O (4.36 g, 20.0 mmol), DMAP (0.33 g, 2.66 mmol), and DIPEA (4.7 mL, 26.6 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 6.84 (s, 1H), 4.14-3.84 (m, 4H), 3.09-2.88 (m, 2H), 2.02-1.86 (m, 2H), 1.79-1.61 (m, 2H), 1.47 (s, 9H), 1.33 (s, 9H). (R)-tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydrofuran-3- yl)methyl)carbamate

[C₁₆H₂₀BrCl N₄O₃ + H − Boc]⁺ 331.0; 330.9 16.16 g (91%); light yellow solid; free base SMs: (R)-3-bromo-5-chloro-N-((tetrahydrofuran-3-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (13.6 g, 41.1 mmol), Boc₂O (10.75 g, 49.3 mmol), DMAP (501 mg, 4.11 mmol), Et₃N (6.87 mL, 49.3 mmol), DCM (100 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.13 (s, 1H), 6.77 (s, 1H), 3.91-3.80 (m, 3H), 3.79-3.67 (m, 2H), 3.48 (dd, J = 8.8, 5.5 Hz, 1H), 2.53-2.40 (m, 1H), 2.02-1.90 (m, 1H), 1.65-1.54 (m, 1H), 1.36 (s, 9H). (S)-tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydrofuran-3- yl)methyl)carbamate

[C₁₆H₂₀BrCl N₄O₃ + H − Boc]⁺ 331.0; 331.1 9.8 g (92.5%); yellow solid; free base SMs: (S)-3-bromo-5-chloro-N-((tetrahydrofuran-3-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (8.05 g, 24.2 mmol), Boc₂O (5.56 g, 25.4 mmol), DMAP (295 mg, 2.4 mmol), Et₃N (4.39 mL, 31.4 mmol). ¹H NMR identical to (R)-isomer tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)((1-methylpiperidin-4- yl)methyl)carbamate

[C₁₈H₂₅BrCl N₅O₂ + H]⁺ 458.1; 458.1 0.483 g (70%); pale yellow solid; free base Sms: 3-bromo-5-chloro-N-((1-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.534 g, 1.5 mmol), Boc₂O (0.37 g, 1.7 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.24 (s, 1H), 7.22 (s, 1H), 3.74 (d, J = 7.3 Hz, 2H), 2.91-2.84 (m, 2H), 2.27 (s, 3H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.63-1.49 (m, 1H), 1.32 (s, 9H), 1.31- 1.17 (m, 2H) tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(2-(4-fluoropiperidin-1- yl)ethyl)carbamate

[C₁₈H₂₄BrClF N₅O₂ + H]⁺ 476.1; 476.1 1.0 g (quant.); pale foam; free base SMs: 3-bromo-5-chloro-N-(2-(4-fluoropiperidin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.79 g, 2.1 mmol), Boc₂O (0.91 g, 4.2 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.10 (s, 1H), 6.93 (s, 1H), 4.65-4.37 (m, 1H), 3.94 (t, J = 5.6 Hz, 2H), 2.55 (t, J = 5.6 Hz, 2H), 2.45-2.32 (m, 2H), 2.30-2.14 (m, 2H), 1.59-1.45 (m, 2H), 1.46-1.29 (m, 2H), 1.37 (s, 9H)

Synthesis of N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method F utilizing 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (550 mg, 1.15 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (520 mg, 1.73 mmol), aq K₃PO₄ (2.0 mL, 4.0 mmol) and PdCl₂dppfDCM (94 mg, 0.110 mmol) at 130° C. for 4 h. The crude product was purified by flash chromatography (SiO₂, 10-40% EtOAc/DCM) to give the desired product as a yellow solid (600 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s, 1H), 7.81-7.93 (m, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.92 (br. s., 1H), 5.15-5.62 (m, 2H), 3.97 (dd, J=11.4, 2.9 Hz, 3H), 3.80 (s, 3H), 3.35 (t, J=10.8 Hz, 2H), 2.92 (td, J=7.0, 3.1 Hz, 1H), 2.61 (s, 3H), 2.53 (s, 3H), 2.08-2.23 (m, 1H), 1.57-1.61 (m, 3H), 1.34-1.49 (m, 2H), 0.85-0.93 (m, 2H), 0.56-0.68 (m, 2H); MS ESI [M+H]⁺ 573.5, calcd for [C₃₁H₃₆N₆O₃S+H]⁺ 573.26.

Synthesis of tert-butyl (3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol) and cyclopentamine (0.11 mL, 1.1 mmol, 1.1 equiv) in THF (6 mL) was added DIPEA (0.22 mL, 1.2 mmol, 1.2 equiv). The resulting mixture was microwaved 3 h at 80° C., 1 h at 120° C. and 1 h at 130° C. The reaction was then allowed to cool to room temperature and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over MgSO₄ and concentrated to give the crude product. Crude product was purified by flash chromatography (gradient: EtOAc/hex 5-40%) to give the title compound as a pale yellow solid (420 mg, 85%). NMR ¹H NMR (400 MHz, CDCl3) δ ppm 7.81 (s, 1H), 5.96 (s, 1H), 5.01 (br, s, 1H), 4.43-4.15 (m, 1H), 3.95 (d, J=7.5 Hz, 2H), 3.63 (d, J=7.0 Hz, 2H), 3.43-3.20 (m, 2H), 2.21-2.08 (m, 2H), 1.88-1.60 (m, 7H), 1.56-1.49 (m, 2H), 1.33-1.23 (m, 2H); MS ESI [M+H]⁺ 494.9, calcd for [C₂₂H₃₂BrN₅O₃+H]⁺ 494.2.

The following intermediates were synthesized according to General Method C:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form tert-butyl (3-bromo-5-((2-hydroxy-2- methylpropyl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₁H₃₂BrN₅ O₄ + H]⁺ 498.2; 498.8 810 mg (81%); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (891 mg, 2 mmol), 1-amino-2-methylpropan-2-ol (356 mg, 2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s, 1H), 6.01 (s, 1H), 5.32-5.37 (m, 1H), 3.97-3.92 (m, 2H), 3.63 (d, J = 7.2 Hz, 2H), 3.55 (d, J = 5.6 Hz, 2H), 3.33 (t, J = 10.2 Hz, 2H), 1.87-1.75 (m, 1H), 1.69- 1.62 (m, 2H), 1.37 (s, 9H), 1.33 (s, 6H), 1.31-1.26 (m, 2H). tert-butyl (3-bromo-5- morpholinopyrazolo[1,5- a]pyrimidin-7-yl)(tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₁H₃₀BrN₅ O₄ + H]⁺ 496.1; 496.8 475 mg (96%); light yellow solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (446 mg, 1 mmol), morpholine (0.26 mL, 3 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (s, 1H), 6.22 (s, 1H), 3.91-3.97 (m, 2H), 3.85 (t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.6 Hz, 4H), 6.64 (d, J = 6.8 Hz, 2H), 3.32 (t, J = 11.4 Hz, 2H), 1.87-1.75 (m, 1H), 1.70-1.62 (m, 2H), 1.58 (s, 9H), 1.29 (dd, J = 12.4, 4.8 Hz, 2H). tert-butyl (3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₂H₃₂BrN₅ O₄ + H]⁺ 510.2; 510.9 122 mg (53%); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (200 mg, 0.45 mmol), tetrahydro-2H-pyran-4-amine (55 mg, 0.54 mmol), DIPEA (0.10 mL, 0.57 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s, 1H), 5.93 (s, 1H), 4.97 (d, J = 7.0 Hz, 1H), 4.15 (br, s, 1H), 4.04-3.97 (m, 2H), 3.93 (dd, J = 11.4, 2.6 Hz, 2H), 3.67-3.51 (m, 4H), 3.31 (td, J = 11.7, 1.8 Hz, 2H), 2.12-2.05 (m, 2H), 1.86-1.71 (m, 2H), 1.88-1.68 (m, 2H), 1.57-1.45 (m, 2H), 1.37 (s, 9H). tert-butyl (3-bromo-5- (cyclohexylamino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₃ + H]⁺ 508.2; 508.9 433 mg (85%); yellow solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (446 mg, 1 mmol), cyclopentamine (0.34 mL, 3 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (s, 1 H), 5.92 (s, 1H), 4.96-4.85 (m, 1H), 3.94 (dd, J = 11.4, 2.4 Hz, 2H), 3.63 (d, J = 7.3 Hz, 2H), 3.38-3.25 (m, 2H), 2.15-2.04 (m, 2H), 1.87-1.74 (m, 3H), 1.74- 1.60 (m, 4H), 1.54-1.40 (m, 2H), 1.39-1.34 (m, 9H), 1.34-1.23 (m, 5H). tert-butyl (3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5- a]pyrimidin-7- yl)(isobutyl)carbamate

[C₂₀H₃₀BrN₅ O₃ + H]⁺ 468.2; 468.8 103 mg (58%); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate (150 mg, 0.37 mmol), 4-aminotetrahydropyran (45 mg, 0.44 mmol), DIPEA (84 μL, 0.48 mmol) ¹H NMR (400 MHz, CDCl₃) 7.82 (s, 1H), 5.94 (s, 1H), 4.81-4.70 (m, 1H), 4.24-4.13 (m, 1H), 4.06- 3.97 (m, 2H), 3.66-3.51 (m, 4H), 2.16-2.07 (m, 2H), 1.90-1.78 (m, 1H), 1.59-1.52 (m, 1H), 1.38 (s, 9 H), 0.92 (d, J = 6.8 Hz, 6H). (R)-tert-butyl (3-bromo-5-((1- hydroxybutan-2- yl)amino)pyrazolo[1,5-a]pyrimidin- 7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₁H₃₂BrN₅ O₄ + H]⁺ 498.2; 498.8 115 mg (51.8%); Colorless thick oil SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (200 mg, 0.45 mmol), R(−)-2-aminobutan-1-ol (85 mmL, 0.90 mmol), DIPEA (156 mmL, 0.90 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 6.00 (s, 1H), 5.22 (d, J = 6.8 Hz, 1H), 4.08-4.02 (m, 1H), 3.95-3.84 (m, 4H), 3.71-3.67 (m, 1H), 3.62 (d, J = 7.2 Hz, 2H), 3.31 (t, J = 11.6 Hz, 2H), 1.83- 1.56 (m, 4H), 1.37 (s, 9H), 1.31-1.20 (m, 3H), 1.03 (t, J = 7.4 Hz, 3H). tert-butyl (3-bromo-5-(((2S,3S)-2- hydroxypentan-3- yl)amino)pyrazolo[1,5-a]pyrimidin- 7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₂H₃₄BrN₅ O₄ + H]⁺ 512.2; 512.9 145 mg (31.5%); White foam Starting materials: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate (400 mg, 0.90 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (250 mg, 1.79 mmol), DIPEA (625 mmL, 3.59 mmol), 1,4-Dioxane (10 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 6.00 (s, 1H), 5.27 (br, s, 1H), 3.98-3.92 (m, 4H), 3.62 (d, J = 7.2 Hz, 2H), 3.35-3.29 (m, 2H), 2.96 (s, 1 H),1.84-1.72 (m, 2H), 1.70-1.61 (m, 3H), 1.37 (s, 9H), 1.30-1.25 (m, 4H), 1.00 (t, J = 7.2 Hz, 3H). tert-butyl (3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)(2-((tert- butoxycarbonyl)oxy)-2- methylpropyl)carbamate

[C₂₅H₃₈BrN₅ O₆ + H]⁺ 584.2; 584.9 159 mg (70%); clear oil; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate (200 mg, 0.39 mmol), 4-aminotetrahydropyran (79 mg, 0.78 mmol), DIPEA (137 μL, 0.78 mmol). (1r,4r)-4-(((3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)(4- methoxybenzyl)amino)methyl) cyclohexanol

[C₂₆H₃₄BrN₅ O₃ + H]⁺ 544.2; 544.2 179 mg (73%); white solid; free base SMs: (1r,4r)-4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)methyl) cyclohexanol (215 mg, 0.45 mmol), tetrahydro-2H-pyran-4-amine (0.453 g, 4.5 mmol) in dioxane (4 mL) at 170° C. for 8 h. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82 (s, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.17 (s, 1H), 4.83 (s, 2H), 4.05-3.89 (m, 3H), 3.79 (s, 3H), 3.63-3.46 (m, 3H), 3.42 (d, J = 6.3 Hz, 2 H), 2.06-1.87 (m., 4H), 1.80-1.60 (m, 3H), 1.57-1.39 (m, 2H), 1.30-1.11 (m, 2H), 1.01-0.88 (m, 2H). tert-butyl(3-bromo-5-(((2S,3S)-2- hydroxypentan-3- yl)amino)pyrazolo[1,5-a]pyrimidin- 7-l)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₄ + H]⁺ 512.2; 512.3 9.55 g (84%); off white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (10.0 g, 22 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (4.7 g, 33 mmol), DIPEA (15.6 mL, 89 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm .80 (s, 1H), 5.99 (s, 1H), 5.14 (br.s, 1H), 4.00-3.93 (m, 4H), 3.62 (d, J = 7.2 Hz, 2H), 3.33 (td, J = 12 Hz, 2.0 Hz, 2H), 2.69 (br. s, 1H), 1.84-1.73 (m, 2H), 1.71-1.63 (m, 3H), 1.37 (s, 9H), 1.34-1.27 (m, 5H), 1.01 (t, J = 7.2 Hz, 3H). (S)-tert-butyl(3-bromo-5-((1- hydroxy-3-methylbutan-2- yl)amino)pyrazolo[1,5-a]pyrimidin- 7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₂H₃₄BrN₅ O₄ + H]⁺ 512.2; 512.2 6.02 g (88%); off white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (6.0 g, 13.4 mmol), (S)-2-amino-3-methylbutan-1-ol (2.08 g, 20.2 mmol), DIPEA (7.02 mL, 40.3 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 6.05 (s, 1H), 5.38 (d, J = 6.4 Hz, 1H), 3.93-3.90 (m, 2H), 3.85-3.83 (m, 2H), 3.74-3.69 (m, 1H), 3.61 (d, J = 7.6 Hz, 2H), 3.30 (t, J = 11.6 Hz, 2H), 2.02- 1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.65-1.58 (m, 2H), 1.37 (s, 9H), 1.31-1.27 (m, 1 H), 0.99 (t, J = 6.4 Hz, 6H). tert-butyl (3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-7-yl) ((tetrahydro- 2H-pyran-4-yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₄ + H]⁺ 524.2; 524.1 8.0 g (97%); cream solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (7.0 g, 15.0 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (3.58 g, 23.0 mmol), DIPEA (10.95 mL, 62.0 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.77 (s, 1H), 6.00 (s, 1H), 5.49 (br. s, 1H), 4.16 (br. s, 1H), 4.07- 4.04 (m, 1H), 3.92 (dd, J = 11.6 Hz, 2.8 Hz, 2H), 3.60 (d, J = 7.2 Hz, 2H), 3.31 (td, J = 11.6 Hz, 2.0 Hz, 2H), 1.82-1.77 (br. m, 3H), 1.72-1.58 (br. m, 6H), 1.49-1.41 (br. m, 2H), 1.36 (s, 9H), 1.30-1.23 (m, 2 H). (S)-tert-butyl(3-bromo-5-((2- hydroxy-2,4-dimethylpentan-3- yl)amino)pyrazolo[1,5-a]pyrimidin- 7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₄H₃₈BrN₅ O₄ + H]⁺ 540.2; 540.2 5.50 g (60%); off white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (7.5 g, 16.8 mmol), (S)-3-amino-2,4-dimethylpentan-2-ol hydrochloride (4.24 g, 25.2 mmol), DIPEA (11.7 mL, 67.2 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (s, 1H), 6.04 (s, 1H), 3.97-3.93 (m, 2H), 3.63 (d, J = 7.2 Hz, 2H), 3.36-3.30 (m, 2H), 2.31-2.24 (m, 1H), 1.85-1.79 (m, 1H), 1.76-1.58 (m, 3H), 1.37-1.34 (m, 14H), 1.33-1.27 (m, 5H) , 0.99 (d, J = 6.8 Hz, 6H). (S)-tert-butyl(3-bromo-5-((1- cyclopropyl-2-hydroxy-2- methylpropyl)amino)pyrazolo [1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₄H₃₆BrN₅ O₄ + H]⁺ 538.2; 538.3 7.50 g (83%); cream solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (7.0 g, 15.0 mmol), (S)-1-amino-1-cyclopropyl-2-methylpropan-2-ol hydrochloride (4.89 g, 25.0 mmol), DIPEA (11.7 mL, 67.3 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 6.01 (s, 1H), 5.25 (d, J = 7.2 Hz, 1H), 3.95 (dd, J = 11.6 Hz, 2.4 Hz, 2H), 3.61 (d, J = 7.2 Hz, 2H), 3.39-3.30 (m, 3H), 1.86-1.73 (m, 1H), 1.69-1.62 (m, 2H), 1.38 (s, 14 H), 1.34-1.25 (m, 4H), 1.06-0.99 (m, 1H), 0.79-0.74 (m, 1H), 0.56-0.50 (m, 2H), 0.41-0.39 (m, 1H). tert-butyl(3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-7- yl)(cyclopropylmethyl)carbamate

[C₂₁H₃₀BrN₅ O₃ + H]⁺ 480.2; 480.3 8.5 g (79%); beige solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(cyclopropylmethyl)carbamate (9.0 g, 22.5 mmol), (1R,2S)-2-aminocyclohexanol.HCl (4.08 g, 27.0 mmol), DIPEA (3.47 g, 25.1 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (s, 1H), 6.08 (s, 1H), 5.33-5.19 (m, 1H), 4.26-4.14 (m, 1H), 4.13-4.06 (m, 1H), 3.61 (d, J = 7.3 Hz, 2H), 2.51 (br. s, 1H), 1.89-1.62 (m, 8H), 1.55-1.45 (m, 2H), 1.40 (s, 9H), 1.06-0.95 (m, 1H), 0.47-0.38 (m, 2H), 0.17-0.07 (m, 2H). tert-butyl (3-bromo-5- (cyclopentylamino)pyrazolo[1,5- a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3- methylcyclobutyl)methyl)carbamate

[C₂₇H₄₀BrN₅ O₅ + H]⁺ 594.2; 594.3 0.40 g (67%); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.45 g, 0.83 mmol), cyclopentylamine (0.085 g, 1.0 mmol), DIPEA (0.21 g, 1.66 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 5.94 (s, 1H), 5.08 (br. s, 1H), 4.23 (br. s, 1H), 3.85- 3.72 (m, 2H), 2.28-2.06 (m, 5H), 2.02-1.89 (m, 2H), 1.81-1.61 (m, 5H), 1.48 (s, 4H), 1.44 (s, 9H), 1.36 (s, 9H). tert-butyl (3-bromo-5-((1- (hydroxymethyl)cyclopentyl)amino) pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₄ + H]⁺ 524.2; 524.3 10.6 g (75%); yellow solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (12.0 g, 26.9 mmol), (1- aminocyclopentyl)methanol (4.64 g, 40 mmol), DIPEA (9.6 mL, 54 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.75 (s, 1H), 6.36 (br. s, 1H), 6.06 (s, 1H), 5.96 (s, 1H), 3.89 (dd, J = 11.3, 2.8 Hz, 2H), 3.67 (d, J = 4.0 Hz, 2H), 3.59 (d, J = 7.3 Hz, 2H), 3.27 (t, J = 11.5 Hz, 2H), 1.94 (d, J = 7.8 Hz, 2H), 1.83-1.53 (m, 8H), 1.39 (s, 9H), 1.33-1.17 (m, 3H). tert-butyl (3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-7-yl)(((R)- tetrahydrofuran-3- yl)methyl)carbamate

[C₂₂H₃₂BrN₅ O₄ + H]⁺ 510.2; 510.3 9.14 g (90%); white solid; free base SMs: (R)-tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydrofuran-3- yl)methyl)carbamate (2.155 g, 5 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (1.137 g, 7.5 mmol), DIPEA (3.3 mL, 20 mmol), NMP (12 mL), in each vial, 4 vials in total. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s, 1H), 5.99 (s, 1H), 5.31 (br. s., 1H), 4.26-4.15 (m, 1H), 4.10 (br. s., 1H), 3.90-3.66 (m, 6H), 3.50 (dd, J = 8.8, 5.5 Hz, 1H), 2.56-2.45 (m, 1H), 1.97 (dd, J = 12.5, 5.3 Hz, 1H), 1.89-1.56 (m, 7H), 1.51 (d, J = 4.3 Hz, 2H), 1.41-1.35 (m, 9H). tert-butyl (3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-7-yl)(((S)- tetrahydrofuran-3- yl)methyl)carbamate

[C₂₂H₃₂BrN₅ O₄ + H]⁺ 510.2; 510.2 453 mg (89%); white solid; free base SMs: (S)-tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydrofuran-3- yl)methyl)carbamate (431mg, 1 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (303 mg, 2 mmol), DIPEA (0.66 mL, 4 mmol) ¹H NMR identical to (R)-isomer

Synthesis of tert-butyl (3-bromo-5-(cyclopentyloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl) ((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol) and cyclopentan-ol (129 mg, 1.5 mmol, 1.5 equiv) in DMF (8 mL) at 0° C. was added 60% NaH (160 mg, 4 mmol, 4 equiv). The resulting mixture was stirred at rt for 1 h. After cooling to 0° C., quenching with satd NH₄Cl and H₂O, it was extracted with EtOAc and purified by flash chromatography (gradient: EtOAc/hex 0-35%) to give the title compound (224 mg, 45%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 6.19 (s, 1H), 5.59-5.68 (m, 1H), 3.94 (dd, J=11.3, 3.3 Hz, 2H), 3.64 (d, J=7.3 Hz, 2H), 3.37-3.26 (m, 2H), 2.15-2.01 (m, 2H), 1.92-1.75 (m, 5H), 1.73-1.59 (m, 4H), 1.36 (s, 9H), 1.30 (dd, J=12.7, 4.1 Hz, 2H).

The following intermediates were synthesized according to General Method D:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form tert-butyl (3-bromo-5-((tetrahydro- 2H-pyran-4-yl)oxy)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₂H₃₁BrN₄ O₅ + H]⁺ 511.2; 511.9 158 mg (69%); clear oil; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (200 mg, 0.45 mmol), tetrahydro-2H-pyran-4-ol (84 mg, 0.82 mmol), 60% NaH (72 mg, 1.8 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.94 (s, 1 H), 6.24 (s, 1H), 5.51-5.42 (m, 1H), 4.07-3.88 (m, 4H), 3.66 (d, J = 7.3 Hz, 2H), 3.46-3.25 (m, 4H), 3.08-2.96 (m, 1H), 2.22-2.12 (m, 2H), 1.92-1.79 (m, 2H), 1.64 (t, J = 13.6 Hz, 4H), 1.37 (s, 9H). 3-bromo-5-chloro-7-((tetrahydro- 2H-pyran-4-yl)methoxy) pyrazolo[1,5-a]pyrimidine

[C₁₂H₁₃BrCl N₃O₂ + H]⁺ 347.99; 348.0 770 mg (100%); white solid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (585 mg, 2.2 mmol), (tetrahydro-2H-pyran-4- yl)methanol (280 mg, 2.4 mmol), 60% NaH (263 mg, 6.6 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.25 (s, 1H), 4.23 (d, J = 7.0 Hz, 2H), 4.06 (dd, J = 11.2, 4.1 Hz, 2H), 3.48 (td, J = 12.0, 2.0 Hz, 2H), 2.47-2.28 (m, 1H), 1.87 (d, J = 11.8 Hz, 2H), 1.55-1.45 (m, 2H). tert-butyl (3-bromo-5- (cyclohexyloxy)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₃H₃₃BrN₄ O₄ + H]⁺ 509.2; 509.9 281 mg (62%); white solid; free base SMs tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (400 mg, 0.89 mmol), cyclohexanol (134 mg, 1.34 mmol), 60% NaH (72 mg, 2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 6.21 (s, 1 H), 5.23-5.33 (m, 1H), 3.94 (d, J = 11.0 Hz, 2H), 3.65 (d, J = 7.0 Hz, 2H), 3.39-3.26 (m, 2 H), 2.06 (br, s, 2H), 1.82 (dd, J = 7.3, 3.8 Hz, 3 H), 1.70-1.44 (m, 8H), 1.42-1.23 (m, 11H).

Synthesis of tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-21-pyran-4-yl)methyl)carbamate

Using Phenol:

To a solution of tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (2.01 g, 4.51 mmol) and phenol (1.27 g, 13.53 mmol, 3 equiv) in DMF (15 mL) was added K₂CO₃ (1.84 g, 13.53 mmol, 3 equiv). The resulting mixture was stirred O/N at rt and quenched with H₂O (150 mL). After extracting with EtOAc (60 mL×2), it was concentrated to dryness and purified by flash chromatography twice (gradient: EtOAc/DCM 0-50%; EtOAc/hex 30-80%) to give the desired product (2.09 g, 92%) as white foam. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.49-7.44 (m, 2H), 7.33-7.28 (m, 3H), 6.44 (s, 1H), 3.98-3.92 (m, 2H), 3.70 (d, J=7.2 Hz, 2H), 3.33 (t, J=11.8 Hz, 2H), 1.90-1.78 (m, 1H), 1.70-1.62 (m, 2H), 1.37 (s, 9H), 1.32 (dd, J=12.8, 4.8 Hz, 2H).

Using Phenoxide:

To a solution of tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (4.55 g, not very dry, assuming 10 mmol) in DMF (20 mL) in was added PhONa (1.22 g, 10.5 mmol). The resulting mixture was stirred at rt for 30 min and quenched with H₂O (200 mL). The precipitates were collected by suction filtration and dried to give the desired product (3.88 g) as white solid.

The following intermediates were synthesized according to General Method E:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(2-methoxyethyl)carbamate

[C₂₀H₂₃BrN₄ O₄ + H]⁺ 463.1; 463.6 3.20 g (quantitative); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate (2.71 g, 6.69 mmol), PhOH (1.23 g, 13.4 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.49-7.43 (m, 2H), 7.32-7.27 (m, 3H), 6.61 (s, 1H), 3.94 (t, J = 5.0 Hz, 2H), 3.59 (t, J = 5.0 Hz, 2H), 3.22 (s, 3H), 1.38 (s, 9H). tert-butyl (3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(2-methoxyethyl)carbamate

[C₁₉H₂₂BrN₅ O₄ + H]⁺ 464.1; 464.7 261 mg (56%); light brown oil; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate (406 mg, 1 mmol), 3-hydroxypyridine (190 mg, 2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.61 (d, J = 2.8 Hz, 1H), 8.49 (dd, J = 4.8, 1.2 Hz, 1H), 7.94 (s, 1H), 7.74-7.69 (m, 1H), 7.37 (dd, J = 8.4, 4.8 Hz, 1H), 6.68 (s, 1H), 3.92 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.0 Hz, 2H), 3.22 (s, 3H), 1.35 (s, 9H). tert-butyl (3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₂H₂₆BrN₅ O₄ + H]⁺ 504.1; 504.8 485 mg (96%); light brown foam; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (446 mg, 1 mmol), 3-hydroxypyridine (190 mg, 2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.63 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 4.8, 1.2 Hz, 1H), 7.95 (s, 1H), 7.76-7.72 (m, 1H), 7.39 (dd, J = 8.6, 4.8 Hz, 1H), 6.51 (s, 1H), 3.98-3.88 (m, 2H), 3.70 (d, J = 7.2 Hz, 2H), 3.30 (t, J = 7.2 Hz, 2H), 1.88-1.76 (m, 1H), 1.68-1.61 (m, 2H), 1.40-1.25 (m, 11H; s, 9H at 1.34 and m, 2H). tert-butyl (3-bromo-5-(3- fluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₃H₂₆BrFN₄ O₄ + H]⁺ 521.1; 521.8 487 mg (94%); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl) carbamate (446 mg, 1 mmol), 3-fluorophenol (224 mg, 2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.99 (s, 1H), 7.45-7.39 (m, 1H), 7.15-7.09 (m, 2H), 7.06-6.99 (m, 1H), 6.46 (s, 1H), 3.98-3.82 (m, 2H), 3.71 (d, J = 6.8 Hz, 2H), 3.33 (t, J = 7.2 Hz, 2H), 1.90-1.78 (m, 1H), 1.70-1.63 (m, 2H) 1.38 (s, 9H), 1 32 (dd, J = 12.6, 3.8 Hz, 2H). tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(2-morpholinoethyl)carbamate

[C₂₃H₂₈BrN₅ O₄ + H]⁺ 518.1; 518.8 3.60 g (99%); white foam; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (3.22 g, 7.0 mmol), PhONa (893 mg, 0.77 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 7.50-7.44 (m, 2H), 7.32-7.26 (m, 3H), 6.52 (s, 1H), 3.94 (t, J = 6.0 Hz, 2H), 3.40-3.33 (m, 4H), 2.56 (t, J = 6.0 Hz, 2H), 2.33-2.27 (m, 4H), 1.38 (s, 9H). 3-bromo-5-phenoxy-7-((tetrahydro- 2H-pyran-4-yl)methoxy) pyrazolo[1,5-a]pyrimidine

[C₁₈H₁₈BrN₃ O₃ + H]⁺ 404.1; 404.6 241 mg (83%); white solid; free base SMs: 3-bromo-5-chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine (250 mg, 0.72 mmol), sodium phenoxide (92mg, 0.79 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1 H), 7.49-7.40 (m, 2H), 7.31-7.27 (m, 3H), 5.88 (s, 1H), 4.17 (d, J = 6.5 Hz, 2H), 4.06 (dd, J = 11.5, 3.3 Hz, 2H), 3.48 (t, J = 11.3 Hz, 2 H), 2.45-2.29 (m, 1H), 1.87 (d, J = 11.3 Hz, 2H), 1.54-1.45 (m, 2H). tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(3-morpholinopropyl)carbamate

[C₂₄H₃₀BrN₅ O₄ + H]⁺ 534.2; 534.1 374 mg (quantitative); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(3-morpholinopropyl)carbamate (200 mg, 0.42 mmol), PhONa (53 mg, 0.46 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.51-7.42 (m, 2H), 7 35-7.21 (m, 3H), 6.47 (s, 1H), 3.86 (t, J = 7.3 Hz, 2H), 3.63 (t, J = 4.5 Hz, 4H), 2.41-226 (m, 6H), 1.88-1.74 (m, 2H), 1.38 (s, 9H). tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(2-(tetrahydro-2H-pyran-4- yl)ethyl)carbamate

[C₂₄H₂₉BrN₄ O₄ + H]⁺ 517.1; 517.9 192 mg (85%); white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4- yl)ethyl)carbamate (200 mg, 0.44 mmol), PhONa (56 mg, 0.48 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.51-7.43 (m, 2H), 7.33-7.28 (m, 3H), 6.43 (s, 1H), 3.94 (dd, J = 11.7, 3.9 Hz, 2H), 3.87-3.80 (m, 2H), 3.35 (t, J = 11.2 Hz, 2H), 1.62-1.49 (m, 5H), 1.39 (s, 9H), 1.35-1.25 (m, 2H). tert-butyl (3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(2-(tetrahydro-2H-pyran-4- yl)ethyl)carbamate

[C₂₃H₂₈BrN₅ O₄ + H]⁺ 518.1; 518.8 190 mg (84%); off-white solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4- yl)ethyl)carbamate (200 mg, 0.44 mmol), pyridin-3-ol (124 mg, 1.31 mmol), K₂CO₃ (241 mg, 1.747 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.66 (d, J = 2.5 Hz, 1H), 8.56 (dd, J = 4.8, 1.3 Hz, 1H), 7.99 (s, 1H), 7.77 (ddd, J = 8.2, 2.7, 1.4 Hz, 1H), 7.43 (dd, J = 8.3, 4.8 Hz, 1H), 6.52 (s, 1H), 3.94 (dd, J = 11.0, 3.8 Hz, 2H), 3.89-3.80 (m, 2H), 3.35 (t, J = 11.0 Hz, 2H), 1.68-1.49 (m, 5H), 1.44-1.37 (m, 9H), 1.37-1.21 (m, 2H). tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate

[C₂₆H₃₃BrN₄ O₆ + H]⁺ 577.2; 577.9 115 mg (54%); light brown solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate (190 mg, 0.37 mmol), NaOPh (51 mg, 0.44 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 7.47-7.40 (m, 2H), 7.33-7.24 (m, 3H), 6.51 (s, 1H), 4.07 (s, 2H), 1.57 (s, 6H), 1.34 (s, 9H) 1.25 (s, 9H). tert-butyl (3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(isobutyl)carbamate

[C₂₀H₂₄BrN₅ O₃ + H]⁺ 462.1; 462.8 132 mg (77%); light brown oil; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate (150 mg, 0.37 mmol), 3-hydroxypyridine (176 mg, 1.85 mmol), DBU (281 mg, 1.85 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.65 (s, 1H), 8.57-8.51 (m, 1H), 7.99 (s, 1H), 7.79-7.72 (m, 1H), 7.45-7.39 (m, 1H), 6.53 (s, 1H), 3.65 (d, J = 7.3 Hz, 2H), 1.93-1.82 (m, 1H), 1.43-1.30 (m, 9H), 0.95 (d, J = 6.8 Hz, 6H). tert-butyl (3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate

[C₂₅H₃₂BrN₅ O₆ + H]⁺ 578.2; 578.9 120 mg (53%); light brown oil; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate (200 mg, 0.39 mmol), 3-hydroxypyridine (183 mg, 1.93 mmol), DBU (293 mg, 1.93 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.65 (s, 1 H), 8.56-8.50 (m, 1H), 7.97 (s, 1H), 7.79-7.71 (m, 1H), 7.44-7.37 (m, 1H), 6.59 (s, 1H), 4.07 (s, 2H), 1.58 (s, 6H), 1.34 (s, 9H), 1.21 (s, 9H). (1r,4r)-4-(((3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(4- methoxybenzyl)amino)methyl) cyclohexanol

[C₂₇H₂₉BrN₄ O₃ + H]⁺ 537.1/539.1. 537.1/539.1 0.18 g (89%); clear film; free base SMS: (1r,4r)-4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)methyl)- cyclohexanol (180 mg, 0.37 mmol) and PhONa (108 mg, 0.93 mmol), 50° C., 70 min. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.93 (s, 1H), 7.40 (t, J = 8.30 Hz, 2H), 7.24-7.17 (m, 3H), 7.10 (d, J = 8.30 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.56 (s, 1H), 4.96 (s, 2H), 3.80 (s, 3H), 3.55-3.475 (m, 1H), 3.48 (d, J = 6.8 Hz, 2H), 2.00-1.88 (m, 2H), 1.80-1.60 (m, 3H), 1.26-1.10 (m, 2H), 1.05-0.84 (m, 2H) tert-buty1(3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3- methylcyclobutyl)methyl)carbamate

[C₂₇H₃₄BrN₅ O₆ + H]⁺ 604.2; 604.3 0.23 g (46%); yellow solid; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.45 g, 0.83 mmol), 3-hydroxypyridine (0.39 g, 4.14 mmol), DBU (0.63 g, 4.14 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.65 (d, J = 2.8 Hz, 1H), 8.55 (dd, J = 4.6, 1.4 Hz, 1H), 7.98 (s, 1H), 7.78-7.73 (m, 1H), 7.46-7.40 (m, 1H), 6.50 (s, 1H), 3.89 (d, J = 6.8 Hz, 2H), 2.30-2.15 (m, 3H), 2.02-1.93 (m, 2H), 1.50 (s, 3H), 1.45 (s, 9H), 1.38 (s, 9H). tert-butyl4-(((3-bromo-5-(3- fluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)(tert- butoxycarbonyl)amino)methyl)-4- fluoropiperidine-1-carboxylate

[C₂₈H₃₄BrF₂ N₅O₅ + H]⁺ 638.2; 638.2 7.8 g (97%); pale yellow solid; free base SMs: tert-butyl 4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(tert- butoxycarbonyl)amino)methyl)-4-fluoropiperidine-1-carboxylate (7.04 g, 12.6 mmol), 3- fluorophenol (2.0 g, 17.6 mmol), K₂CO₃ (3.47 g, 25.1 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.46-7.37 (m, 1H), 7.16-7.07 (m, 2H), 7.05-6.95 (m, 1H), 6.55 (s, 1H), 4.14-3.85 (m, 4H), 3.11-2.92 (m, 2H), 2.02-1.86 (m, 2H), 1.81-1.62 (m, 2H), 1.47 (s, 9H), 1.35 (s, 9H). tert-butyl (3-bromo-5-(3- fluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)(2- morpholinoethyl)carbamate

[C₂₃H₂₇BrFN₅ O₄ + H]⁺ 536.1; 536.2 5.42 g (quant.); light brown foam; free base SMs: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (4.61 g, 10 mmol), 3-fluorophenol (2.24 g, 20 mmol), K₂CO₃ (2.76 g, 20 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.94 (s, 1H), 7.42-7.35 (m, 1H), 7.10-7.02 (m, 2H), 7.00-6.95 (m, 1H), 6.54 (s, 1H), 3.92 (t, J = 5.8 Hz, 2H), 3.35-3.28 (m, 4H), 2.55 (t, J = 5.8 Hz, 2H), 2.27 (t, J = 4.2 Hz, 4H), 1.36 (s, 9H). tert-butyl (3-bromo-5-(2,3- difluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)(2- morpholinoethyl)carbamate

[C₂₃H₂₆BrF₂ N₅O₄ + H]⁺ 554.1; 554.1 532 mg (100%); white solid; free base SMS: tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (mg, 1 mmol), 2,3-difluorophenol (390 mg, 3 mmol), K₂CO₃ (552 mg, 4 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1 H), 7.18-7.18 (m, 3 H), 6.64 (s, 1 H), 3.97 (t, J = 5.6 Hz, 2 H), 3.32 (br. s., 4 H), 2.58 (t, J = 5.8 Hz, 2 H), 2.29 (t, J = 4.4 Hz, 4 H), 1.39 (s, 9 H). tert-butyl (3-bromo-5-(3- fluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)((1-methylpiperidin- 4-yl)methyl)carbamate

[C₂₄H₂₉BrFN₅ O₃ + H]⁺ 533.1 534.1 0.338 g (60%); light grey solid; free base Sms: (General Method E)_ tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((1- methylpiperidin-4-yl)methyl)carbamate (0.483 g, 1.05 mmol), 3-fluorophenol (0.413 g, 3.7 mmol), K₂CO₃ (0.44 g, 3.2 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.05 (s, 1H), 7.55-7.39 (m, 1H), 7.20-7.13 (m, 2H), 7.07 (dd, J = 2.5, 0.8 Hz, 1H), 6.83 (s, 1H), 3.72 (d, J = 7.3 Hz, 2H), 2.84 (d, J = 11.8 Hz, 2H), 2.23 (s, 3H), 2.00-1.88 (m., 2H), 1.85-1.76 (m, 2H), 1.65-1.50 (m, 1H), 1.35 (s, 9H), 1.33-1.22 (m, 2H) tert-butyl (3-bromo-5-(2,3- difluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)(2-(4-fluoropiperidin- 1-yl)ethyl)carbamate

[C₂₄H₂₇BrF₃ N₅O₃ + H]⁺ 570.1 570.3 0.289 g (68%); pale foam; free base Sms: (General Method E)_tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-(4- fluoropiperidin-1-yl)ethyl)carbamate (0.354 g, 0.74 mmol), 2,3-difluorophenol (0.288 g, 2.2 mmol), K₂CO₃ (0.31 g, 2.2 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.21-7.07 (m, 3H), 6.66 (s, 1H), 4.65-4.43 (m, 1H), 3.95 (t, J = 5.8 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 2.48-2.36 (m, 2H), 2.31-2.20 (m, 2H), 1.45-1.34 (m, 4H), 1.39 (s, 9H)

The following intermediates were synthesized according to General Method F (Suzuki):

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form 2-chloro-N-cyclopropyl-4-(4-((4- methoxybenzyl) ((tetrahydro-2H-pyran-4- yl)methyl)amino)-2- (methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₃₀H₃₃ClN₆ O₃S + H]⁺ 593.2; 593.7 1.3 g (68%); yellow solid; free base SMs: 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-atetrahydro-2H-pyran-4-yl)methyl)pyrazolo [1,5-a][1,3,5]triazin-4-amine (1.6 g, 3.3 mmol), (3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (0.87 g, 3.6 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s, 1 H), 8.19 (d, J = 1.5 Hz, 1 H), 7.94 (dd, J = 8.0, 2.0 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.23 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 6.50 (br. s., 1 H), 5.32 (br. s, 2 H), 3.97 (d, J = 11.0 Hz, 2 H), 3.81 (s, 3 H), 3.29-3.41 (m, 2 H), 2.92-3.00 (m, 1 H), 2.62 (s, 3 H), 2.09-2.19 (m, 1 H), 1.58-1.66 (m, 4 H), 1.36-1.49 (m, 2 H), 0.87-0.95 (m, 2 H), 0.64-0.72 (m, 2 H). N-cyclopropyl-4-(4-((4- methoxybenzyl)(2- morpholinoethyl)amino)-2- (methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₃₀H₃₅IN₇O₃ S + H]⁺ 574.3; 574.5 1.3 g (68%); yellow solid; free base SMS: 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-(2-morpholinoethyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine (1.10 g, 2.28 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (982 mg, 3.42 mmol). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.38-5.22 (m, 2H), 4.15-4.00 (m, 2H), 3.78 (s, 3H), 3.68-3.57 (m, 4H), 2.96-2.86 (m, 1H), 2.64 (t, J = 6.6 Hz, 2H), 2.56 (s, 3H), 2.52-2.38 (m, 4H), 0.90- 0.80 (m, 2H), 0.66-0.60 (m, 2H). N-cyclopropyl-4-(4-((4- methoxybenzyl)(3- morpholinoethyl)amino)-2- (methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₃₁H₃₇N₇O₃ S + H]⁺ 588.3; 588.2 1.3 g (68%); pale solid; free base SMs: 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-(3-morpholinopropyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine (1.6 g, 3.156 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (1.359 g, 4.734 mmol). ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1 H), 8.10 (d, J = 8.5 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.25 (br. s., 1 H), 5.15-5.52 (br. s., 2 H), 3.88-4.11 (br. s., 2 H), 3.81 (s, 3 H), 3.70 (t, J = 4.6 Hz, 4 H), 2.89-2.99 (m, 1 H), 2.61 (s, 3 H), 2.32-2.47 (m, 6 H), 1.87-1.97(m, 2 H), 0.86-0.94 (m, 2 H), 0.61-0.68 (m, 2 H). N-cyclopropyl-4-(4-((4- methoxybenzyl)((tetrahydro-2H-pyran- 4-yl)methyl)amino)-2- (methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₃₀H₃₄N₆O₃ S + H]⁺ 559.2; 559.5 815 mg (70%); white solid; free base SMs: 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4- yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 g, 2.09 mmol), N-cyclopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (900 mg, 3.14 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24 (s, 1 H), 8.09 (d, J = 8.3 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.26 (br. s., 1 H), 5.36 (br. s., 1 H), 3.97 (dd, J = 11.2, 3.1 Hz, 3 H), 3.80 (s, 3 H), 3.35 (t, J = 11.2 Hz, 1 H), 2.93 (s, 1 H), 2.61 (s, 3 H), 2.06-2.20 (m, 1 H), 1.54-1.66 (m, 2 H), 1.35-1.48 (m, 2 H), 0.83-0.93 (m, 2 H), 0.61-0.68 (m, 2 H). N-cyclopropyl-4-(4-((((cis)-4- hydroxycyclohexyl)methyl)(4- methoxybenzyl)amino)-2- (methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₂H₃₈N₆O₃ S + H]⁺ 587.3; 587.2 0.347 g (74%); a cream colored solid; free base SMs: (cis)-4-(((8-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)(4- methoxybenzyl)amino)methyl)cyclohexanol (0.39 g, 0.80 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.37 g, 1.2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1 H), 7.69-7.81 (m, 2 H), 7.27 (d, J = 8.00 Hz, 1 H), 7.13 (d, J = 7.28 Hz, 2 H), 6.77 (d, J = 8.53 Hz, 2 H), 5.05-5.50 (br. s., 2 H), 3.85 (br. s., 1 H), 3.70 (s, 3 H), 3.55-4.05 (br.s. 2H), 2.73-2.84 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3 H), 1.87 (br. s., 1 H), 1.64 (br. s., 2 H), 1.33-1.49 (m, 6 H), 0.71-0.80 (m, 2 H), 0.53 (br. s., 2 H). N-cyclopropyl-4-(4-((4- methoxybenzyl)(2- morpholinoethyl)amino)-2- (methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₁H₃₇N₇O₃ S + H]⁺ 588.3; 588.2 0.34 g (94%); light yellow solid; free base SMs: 8-bromo-N-(4-methoxy benzyl)-2-(methylthio)-N-(2-morpholinoethyl) pyrazolo[1,5-a][1,3,5] triazin-4-amine (0.30 g, 0.61 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (0.26 g, 0.85 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.36-8.43 (m, 1 H), 7.98-8.03 (m, 1 H), 7.94 (d, J = 7.50 Hz, 1 H), 7.36 (d, J = 8.00 Hz, 1 H), 7.33 (d, J = 8.50 Hz, 2 H), 6.91 (d, J = 8.50 Hz, 2 H), 5.31-5.37 (br.s., 2 H), 4.13-4.20 (m, 2 H), 3.79 (s, 3 H), 3.54-3.60 (m, 4 H), 2.82-2.92 (m, 1 H), 2.64-2.73 (m, 2 H), 2.60 (s, 3 H), 2.47-2.53 (m, 4 H), 2.46 (s, 3 H), 0.78-0.86 (m, 2 H), 0.58-0.67 (m, 2 H).

Synthesis of N-cyclopropyl-2-methyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method F utilizing N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyraz-olo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (410 mg, 0.72 mmol) in DCM/TFA (2:1, 6 mL) at 60° C. for 30 h. The crude product was purified by flash chromatography (SiO₂, 20-100% EtOAc/DCM) to give the desired product as a yellow solid (320 mg, 100%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (s, 1H), 7.83-7.90 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 6.56 (t, J=6.6 Hz, 1H), 5.90 (br s, 1H), 4.02 (dd, J=11.4, 3.6 Hz, 2H), 3.59 (t, J=6.9 Hz, 2H), 3.42 (t, J=11.7 Hz, 2H), 2.91-2.94 (m, 1H), 2.64 (s, 3H), 2.53 (s, 3H), 1.96-1.99 (m, 1H), 1.73 (d, J=11.8 Hz, 2H), 1.41-1.49 (m, 2H), 0.87-0.92 (m, 2H), 0.62-0.65 (m, 2H); MS ESI [M+H]⁺ 453.5, calcd for [C₂₃H₂₈N₆O₂S+H]⁺ 453.20.

The following intermediates were synthesized according to General Method F (deprotection):

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form 2-chloro-N-cyclopropyl-4-(2- (methylthio)-4-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₅ClN₆O₂S + H]⁺ 473.1; 473.7 1.1 g (100%); brown solid; free base SMs: 2-chloro-N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (1.3 g, 2.3 mmol). N-cyclopropyl-4-(2-(methylthio)-4- ((3- morpholinopropyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₃H₂₉N₇O₂S + H]⁺ 468.3; 468.2 724 mg (79%); yellow solid; free base SMs: N-cyclopropyl-4-(4-((4-methoxybenzyl)(3-morpholinopropyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (1.15 g, 1.96 mmol). ¹H NMR (400 MHz, CDCl₃) δ 9.11 (br. s., 1 H), 8.27 (s, 1 H), 8.09 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 6.25 (br. s., 1 H), 3.93 (t, J = 4.4 Hz, 4 H), 3.79 (d, J = 5.5 Hz, 2 H), 2.90-2.97 (m, 1 H), 2.62- 2.68 (m, 5 H), 2.57 (br. s., 4 H), 1.88 (br. s., 2 H), 0.86-0.94 (m, 2 H), 0.61-0.67 (m, 2 H). N-cyclopropyl-4-(2-(methylthio)-4- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₆N₆O₂S + H]⁺ 439.2; 439.6 561 mg (90%); beige solid; free base SMs: N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (800 mg, 1.43 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s, 1 H), 8.07 (d, J = 8.5 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 6.54-6.62 (m, 1 H), 6.27 (br. s., 1 H), 4.02 (dd, J = 11.0, 3.8 Hz, 2 H), 3.59 (t, J = 6.8 Hz, 2 H), 3.42 (t, J = 12.0 Hz, 2 H), 2.89-2.98 (m, 1 H), 2.64 (s, 3 H), 1.91-2.05 (m, 1 H), 1.68-1.77 (m, 2 H), 1.37- 1.52 (m, 2 H), 0.85-0.93 (m, 2 H), 0.61-0.68 (m, 2 H).

The following intermediates were synthesized according to General Method K:

MS calculated; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form N-cyclopropyl-4-(4-((4- methoxybenzyl)((tetrahydro-2H- pyran-4-yl)methyl)amino)-2- (methylsulfonyl)pyrazolo[1,5- a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₁H₃₆N₆O₅S + H]⁺ 605.25; 605.4 140 mg (89%); yellow solid; free base SMs: N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (150 mg, 0.26 mmol), mCPBA (180 mg, 0.79 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.38 (s, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2 H), 5.91 (br. s., 1 H), 4.97-5.19 (m, 2 H), 4.31-4.53 (m, 2 H), 3.99 (d, J = 8.3 Hz, 2 H), 3.81 (s, 3 H), 3.26-3.45 (m, 5 H), 2.85-3.02 (m, 1 H), 2.53 (s, 3 H), 1.46-1.71 (m, 5 H),0.82-0.99 (m, 2 H), 0.59-0.69 (m, 2 H). 2-chloro-N-cyclopropyl-4-(2- (methylsulfonyl)-4-(((tetrahydro-2H- pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₅ClN₆O₄S + H]⁺ 505.1; 505.6 1.2 g (100%); yellow solid; free base SMs: 2-chloro-N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (1.0 g, 2.1 mmol), mCPBA (1.4g. 6.3 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.39 (s, 1 H), 7.95 (s, 1 H), 7.85 (dd, J = 8.1, 1.5 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.10 (t, J = 6.3 Hz, 1 H), 6.51 (br s, 1 H), 4.05 (dd, J = 11.0, 3.2 Hz, 2 H), 3.74 (t, J = 6.6 Hz, 2 H), 3.38-3.47 (m, 5 H), 2.94-3.00 (m, 1 H), 2.02-2.08 (m, 1 H), 1.75 (d, J = 11.7 Hz, 2 H), 1.44-1.53 (m, 2 H), 0.87-0.96 (m, 2 H), 0.66-0.72 (m, 2 H). N-cyclopropyl-4-(2-(methylsulfonyl)- 4-((3- morpholinopropyl)amino)pyrazolo [1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₃H₂₉N₇O₄S + H]⁺ 500.2; 500.1 126 mg (16%); pale solid; free base SMs: N-cyclopropyl-4-(2-(methylthio)-4-((3-morpholinopropyl)amino)pyrazolo[1,5-a][1,3,5]triazin- 8-yl)benzamide (724 mg, 1.55 mmol), mCPBA (1042 mg, 4.65 mmol). 1H NMR (400 MHz, CDCl3) δ 12.28-12.38 (m, 1 H), 8.29 (s, 1 H), 7.91 (d, J = 8.3 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H), 6.52-6.60 (m, 1 H), 4.53-4.59 (m, 2 H), 3.93 (br. s., 2 H), 3.82 (d, J = 12.0 Hz, 2 H), 3.68 (br. s., 2 H), 3.34 (br. s., 4 H), 2.92-3.04 (m, 4 H), 2.36 (br. s., 2 H), 0.87-0.92 (m, 2 H), 0.71 (br. s., 2 H). N-cyclopropyl-4-(2-(methylsulfonyl)- 4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₆N₆O₄S + H]⁺ 471.2; 471.5 412 mg (69%); white solid; free base SMs: N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide (535 mg, 1.27 mmol), mCPBA (849 mg, 3.8 mmol) N-cyclopropyl-4-(4-((((cis)-4- hydroxycyclohexyl)methyl)(4- methoxybenzyl)amino)-2- (methylsulfonyl)pyrazolo[1,5- a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₂H₃₈N₆O₅S + H]⁺ 619.3; 619.2 0.279 g (76%); white powder; free base SMs: N-cyclopropyl-4-(4-((((cis)-4-hydroxycyclohexyl)methyl)(4-methoxybenzyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (0.347 g, 0.59 mmol), mCPBA (0.397 g, 1.8 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (s, 1 H), 7.83 (d, J = 7.03 Hz, 1 H), 7.77 (s, 1 H), 7.25-7.46 (br.m. 1 H), 7.42 (d, J = 8.03 Hz, 2 H), 6.88 (d, J = 8.28 Hz, 2 H), 5.87-4.98 (m, 2 H), 5.03-5.14 (br.s., 1H), 4.34-4.49 (m, 1 H), 3.96-4.13 (m, 2 H), 3.80 (s, 3 H), 3.35 (br. S., 3 H), 2.87-2.98 (m, 1 H), 2.53 (s, 3 H), 1.79 (br. S., 2 H), 1.56 (br.s, 9 H), 0.84-0.96 (m, 2 H), 0.54-0.71 (m, 2 H).

Synthesis of N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5-a][3,5] triazin-8-yl)benzamide

The title compound was synthesized according to General Method F followed by General Method K. A solution of N-cyclopropyl-4-(4-((4-methoxybenzyl)(2-morpholinoethyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benz-amide (701 mg, 1.22 mmol) in TFA/DCM (5 ml/10 ml) was heated in microwave for 2 h at 80° C. After removal of solvent, it was redissolved DCM (20 ml) and treated with mMCPBA (3 eq). After stirring for 3 h at rt, additional mCPBA (2 eq) was added and it was stirred for 2 h. Solvents were removed and the crude product was purified by flash chromatography (SiO₂, 10-80% EtOAc/DCM then 10-90% MeOH/DCM) to give the desired product as a yellow solid (345 mg, TFA salt, 47%). NMR ¹H NMR (400 MHz, CDCl₃) δ ppm 9.79 (brs, 1H), 9.01 (s, 1H), 8.46 (d, J=4.0 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H), 9.26 (d, J=8.4 Hz, 2H), 4.13-3.00 (m, 15H), 2.90-2.82 (m, 1H), 0.75-0.68 (m, 2H), 0.62-0.56 (m, 2H); MS ESI [M+H]⁺ 486.4, calcd for [C₂₂H₂₇N₇O₄S+H]⁺ 486.2.

Synthesis of N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method E utilizing N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (87 mg, 0.14 mmol), phenol (68 mg, 0.72 mmol), and DBU (0.11 mL, 0.72 mmol) in DME (2 mL) at 100° C. to rt for 1 h. The crude product was purified by flash chromatography (SiO₂, 10-80% EtOAc/DCM) to give the desired product as a white solid (70 mg, 79%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.37-7.46 (m, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.22-7.28 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.3 Hz, 2H), 5.91 (br. s., 1H), 5.66 (d, J=15.8 Hz, 2H), 4.07 (t, J=6.7 Hz, 1H), 3.93 (d, J=9.3 Hz, 2H), 3.80 (s, 3H), 3.29 (t, J11.2 Hz, 2H), 2.90 (td, J=7.0, 3.4 Hz, 1H), 2.42 (s, 3H), 1.96-2.10 (m, 2H), 1.33-1.65 (m, 4H), 0.82-0.91 (m, 2H), 0.55-0.65 (m, 2H); MS ESI [M+H]⁺ 619.5, calcd for [C₃₆H₃₈N₆O₄+H]⁺ 619.30.

Synthesis of N-cyclopropyl-4-(2-(dimethylamino)-4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method C utilizing N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (50 mg, 0.083 mmol) and 2,2,2-trifluoro-1,1-N dimethyl-ethylamine hydrochloride (20 mg, 0.12 mmol) and DIPEA (0.020 mL, 0.12 mmol) in DMF (2 mL) at 100° C. for 18 h. The crude product was purified by RP chromatography (C18 column, 10-90% MeCN/H₂O) to give the desired product as a pale yellow solid (23 mg, 58%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.24 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.34 (br. s., 2H), 3.90 (dd, J=11.2, 3.4 Hz, 4H), 3.76 (s, 3H), 3.21 (s, 6H), 2.84-2.87 (m, 1H), 2.44 (s, 3H), 2.07-2.30 (m, 1H), 1.59 (d, 0.1=12.5 Hz, 2H), 1.19-1.43 (m, 4H), 0.75-0.87 (m, 2H), 0.55-0.69 (m, 2H); MS ESI [M+H]⁺ 570.5, calcd for [C₃₂H₃₉N₇O₃+H]⁺570.31.

Synthesis of N-cyclopropyl-2-methyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method K utilizing N-cyclopropyl-2-methyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (360 mg, 0.80 mmol) and mCPBA (540 mg, 2.39 mmol) in DCM (12 mL) at 0° C. to rt for 2 h. The crude product was purified by flash chromatography (SiO₂, 40-100% EtOAc/DCM) to give the desired product as a pale yellow solid (185 mg, 48%). MS ESI [M+H]⁺ 485.4, calcd for [C₂₃H₂₈N₆O₄S+H]⁺ 485.19.

Synthesis of tert-butyl (3-(4-(cycloproplcarbamoyl)-3-methylphenyl)-5-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

According to General method H, a mixture of sodium benzenesulfinate (1.968 g, 12 mmol, 1.2 equiv) and tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (4.455 g, 10 mmol) in DMF (40 mL) was heated at 60° C. for 2 h. After removal of solvents, it was purified by flash chromatography (gradient: EtOAc/hex 0-80%) to give tert-butyl (3-bromo-5-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl) methyl)carbamate (5.37 g, 97%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 1H), 8.19-8.15 (m, 2H), 7.73-7.69 (m, 1H), 7.65-7.60 (m, 2H), 7.55 (s, 1H), 3.95-3.89 (m, 2H), 3.79 (d, J=7.6 Hz, 2H), 3.33-3.25 (m, 2H), 1.82-1.72 (m, 2H), 1.64-1.57 (m, 2H), 1.36 (s, 9H), 1.30-1.24 (m, 2H). MS ESI [M+H]⁺ 551.1, calcd for [C₂₃H₂₇BrN₄O₅S+H]⁺ 551.1.

According to General method I, to a mixture of the above compound (5.37 g, 9.75 mmol) and N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.11 g, 13.65 mmol, 1.4 equiv) in THF (60 mL) was added 2 M K₃PO₄ (14.6 mL, 29.2 mmol, 3 equiv), followed by PdCl₂dppfDCM (318 mg, 0.39 mmol, 4 mol %). The resulting mixture was purged with Ar and then heated at 60° C. for 1.5 h. It was diluted with brine (30 mL), extracted with EtOAc and combined. After removal of solvents, the residue was purified by flash chromatography (gradient: EtOAc/hex 0-80%) to give the title compound (6.02 g) as yellow foam. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.54 (s, 1H), 8.20-8.17 (m, 2H), 7.77-7.72 (m, 2H), 7.70-7.62 (m, 3H), 7.56 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 3.96-3.91 (m, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.31 (td, J=11.6, 1.8 Hz, 2H), 2.97-2.91 (m, 1H), 2.50 (s, 3H), 1.87-1.67 (m, 1H), 1.68-1.63 (m, 2H), 1.38 (s, 9H), 1.34-1.27 (m, 2H), 0.96-0.89 (m, 2H), 0.68-0.63 (m, 2H). MS ESI [M+H]⁺ 646.2, calcd for [C₃₄H₃₉N₅O₆S+H]⁺ 646.3.

Preparation of Exemplary Compounds of the Invention Example A1. N-Cyclopropyl-4-(2-(dimethylamino)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino) pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method F utilizing N-cyclopropyl-4-(2-(dimethylamino)-4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (23 mg, 0.040 mmol) in DCM:TFA (1 mL:3 mL) at 100° C. for 30 min. Purification by prep-HPLC, followed by trituration with MeOH gave the title compound as a free base (white solid, 8.1 mg, 45%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 7.77-7.93 (m, 2H), 7.37 (d, J=8.5 Hz, 1H), 6.39 (t, J=6.1 Hz, 1H), 5.90 (br. s., 1H), 4.02 (dd, J=11.8, 3.5 Hz, 2H), 3.52 (t, J=6.7 Hz, 2H), 3.41 (t, J=11.5 Hz, 2H), 3.27 (s, 6H), 2.82-2.97 (m, 1H), 2.52 (s, 3H), 1.87-2.06 (m, 1H), 1.73 (d, J=12.8 Hz, 2H), 1.39-1.49 (m, 2H), 0.81-0.96 (m, 2H), 0.56-0.66 (m, 2H); MS ESI [M+H]⁺ 450.5, calcd for [C₂₄H₃₁N₇O₂+H]⁺ 450.25.

Example A2. 4-(2-(Cyclopentylamino)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-N-cyclopropyl-2-methylbenzamide

The title compound was synthesized according to General Method C utilizing N-cyclopropyl-2-methyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (88 mg, 0.18 mmol) and cyclopentylamine (0.040 mL, 0.40 mmol) in THF (5 mL) at 35° C. for 6 h. The crude product was purified by RP chromatography (C18 column, 20-90% MeCN/H₂O) to give the desired product as a white solid (68 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (s, 1H), 7.66-7.96 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 6.45 (br. s., 1H), 5.98 (br. s., 1H), 5.89-6.33 (m, 1H), 5.09 (br. s., 1H), 4.26-4.42 (m, 1H), 4.00 (dd, J=11.2, 3.4 Hz, 2H), 3.45 (br. s., 2H), 3.39 (td, J=11.7, 1.9 Hz, 2H), 2.86-2.93 (m, 1H), 2.50 (s, 3H), 2.12 (br. s., 2H), 1.83-1.99 (m, 2H), 1.69-1.81 (m, 5H), 1.56 (d, J=5.8 Hz, 2H), 1.33-1.47 (m, 2H), 0.78-0.94 (m, 2H), 0.56-0.65 (m, 2H); MS ESI [M+H]⁺490.5, calcd for [C₂₇H₃₅N₇O₂+H]⁺ 490.29.

Example A4. 2-Chloro-N-cyclopropyl-4-(2-phenoxy-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino) pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method E utilizing 2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.20 mmol), phenol (75 mg, 0.79 mmol), and DBU (0.12 mL, 0.79 mol) in DME (4 mL) at 100° C. for 1 h. The crude product was purified by flash chromatography (C18 column, 20-90% MeCN/H₂O) followed by trituration with MeOH to give the desired product as a white solid (34 mg, 33%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (br. s., 1H), 7.89 (br. s., 1H), 7.69 (br. s., 2H), 7.41-7.54 (m, 2H), 7.28-7.37 (m, 3H), 6.74 (br. s., 1H), 6.46 (br. s., 1H), 4.03 (d, J=8.0 Hz, 2H), 3.58 (br. s., 2H), 3.41 (t, J10.2 Hz, 2H), 2.84-3.03 (m, 1H), 1.91-2.11 (m, 1H), 1.71 (d, J=11.8 Hz, 2H), 1.34-1.51 (m, 2H), 0.89 (d, J=6.5 Hz, 2H), 0.57-0.73 (m, 2H); MS ESI [M+H]⁺ 519.6, calcd for [C₂₇H₂₇ClN₆O₃+H]⁺ 519.18.

Example A5. 2-chloro-4-(2-(cyclopentyloxy)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-N-cyclopropylbenzamide

The title compound was synthesized according to General Method D utilizing 2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.20 mmol), NaH (100 mg, 60% in mineral oil, 2.5 mmol), and cyclopentanol (0.040 mL, 0.44 mol) in DMF (4 mL) at 0° C. to rt for 1 h. The crude product was purified by RP chromatography (C18 column, 20-90% MeCN/H₂O) followed by trituration with MeOH to give the desired product as a white solid (48 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.20 (s, 1H), 8.11 (s, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 6.58 (br. s., 1H), 6.48 (br. s., 1H), 5.39-5.62 (m, 1H), 4.02 (d, J=8.0 Hz, 2H), 3.59 (t, J=6.4 Hz, 2H), 3.42 (t, J=10.8 Hz, 2H), 2.96 (d, J=3.5 Hz, 1H), 2.06-2.19 (m, 2H), 1.93-2.05 (m, 3H), 1.81-1.92 (m, 2H), 1.63-1.78 (m, 4H), 1.38-1.51 (m, 2H), 0.84-0.97 (m, 2H), 0.61-0.74 (m, 2H); MS ESI [M+H]⁺ 511.7, calcd for [C₂₆H₃₁ClN₆O₃+H]⁺ 511.21.

Example C1. N-cyclopropyl-4-(4-((3-morpholinopropyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

4-(3-((8-(4-(cyclopropylcarbamoyl)phenyl)-2-phenoxypyrazolo[1,5-a][1,3,5] triazin-4-yl)amino)propyl)-4-hydroxymorpholin-4-ium 2,2,2-trifluoroacetate (42 mg, 0.065 mmol) was converted into free dissolved in CDCl3 before the solution of (pinB)2 (17 mg, 0.065 mmol) in DCM was added dropwise at rt. The resulting reaction mixture was stirred at rt for 5 min followed by removal of solvent. The residue was purified by HPLC to give the title compound (30 mg, 70% yield) as light yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.39 (s, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.42-7.54 (m, 2H), 7.24-7.36 (m, 3H), 4.07 (d, J=12.3 Hz, 2H), 3.81 (t, J=12.3 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H), 3.54 (d, J=12.3 Hz, 2H), 3.21-3.29 (m, 2H), 3.14 (t, J=10.9 Hz, 2H), 2.79-2.90 (m, 1H), 2.08-2.22 (m, 2H), 0.76-0.85 (m, 2H), 0.59-0.68 (m, 2H); MS ESI [M+H]⁺ 514.3, calcd for [C₂₈H₃₁N₇O₃+H]⁺ 514.3.

The following exemplary compounds were synthesized according to General Methods C, D, E or F, as indicated:

MS calculated Yield; MS ESI Appearance; Example/IUPAC name Structure [M + H]⁺ Salt form A3: N-cyclopropyl-2-methyl-4-(2- phenoxy-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₈H₃₀N₆O₃ + H]⁺ 499.2 499.5 131 mg (46%); white solid; free base SMs (method F): N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4- yl)methyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (354 mg, 0.57 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1 H), 7.64 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.39-7.45 (m, 2 H), 7.25-7.31 (m, 3 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.87 (t, J = 6.1 Hz, 1 H), 6.11 (br. s., 1 H), 3.96 (dd, J = 11.4, 3.4 Hz, 2 H), 3.50 (t, J = 6.7 Hz, 2 H), 3.35 (td, J = 11.7, 1.6 Hz, 2 H), 2.87-2.92 (m, 1 H), 2.32 (s, 3 H), 1.87-2.01 (m, 1 H), 1.61-1.70 (m, 2 H), 1.38-1.45 (m, 2 H), 0.79-0.86 (m, 2 H), 0.55-0.61 (m, 2 H). A10: N-cyclopropyl-4-(2-phenoxy-4- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₇H₂₈N₆O₃ + H]⁺ 485.2 485.5 46 mg (45%); white solid; free base SMs (method E): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.21 mmol), phenol (79 mg, 0.84 mmol), DBU (0.13 mL, 0.84 mmol). ¹H NMR (400 MHz, CDCl₃) δ 18.26 (s, 1 H), 7.86 (d, J = 9.3 Hz, 2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.26-7.33 (m, 3 H), 6.84 (br. s., 1 H), 6.24 (br. s., 1 H), 4.01 (dd, J = 11.3, 3.3 Hz, 2 H), 3.51-3.58 (m, 2 H), 3.40 (td, J = 11.8, 2.0 Hz, 2 H), 2.86-2.95 (m, 1 H), 1.92-2.06 (m, 1 H), 1.63-1.75 (m, 2 H), 1.31-1.49 (m, 2 H), 0.82-0.92 (m, 2 H), 0.56-0.69 (m, 2 H). A11: 4-(2-(cyclopentyloxy)-4- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)-N- cyclopropylbenzamide

[C₂₆H₃₂N₆O₃ + H]⁺ 477.25 477.5 39 mg (39%); white solid; free base SMs (method D): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.21 mmol), NaH (44 mg, 60% in mineral oil, 1.11 mmol), and cyclopentanol (0.049 g, 0.57 mol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 1 H), 8.04 (d, J = 8.5 Hz, 2 H), 7.79 (d, J = 8.5 Hz, 2 H), 6.53-6.60 (m, 1 H), 6.24 (br. s., 1 H), 5.47-5.55 (m, 1 H), 4.01 (dd, J = 11.0, 4.0 Hz, 2 H), 3.59 (t, J = 6.4 Hz, 2 H), 3.35-3.46 (m, 2 H), 2.88-2.97 (m, 1 H), 2.04-2.14 (m, 2 H), 1.92-2.02 (m, 3 H), 1.81-1.90 (m, 2 H), 1.69-1.77 (m, 2 H), 1.62-1.69 (m, 2 H), 1.37-1.51 (m, 2 H), 0.85-0.92 (m, 2 H), 0.60-0.67 (m, 2 H). A13: N-cyclopropyl-4-(2-(pyridin-3- yloxy)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)-pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₆H₂₇N₇O₃ + H]⁺ 486.2 486.4 18 mg (18%); white solid; free base SMs (method E): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.21 mmol), 3- hydroxypyridine (79 mg, 0.84 mmol), DBU (0.13 mL, 0.84 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.68 (s, 1 H), 8.56 (d, J = 4.8 Hz, 1 H), 8.28 (d, J = 1.3 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 2 H), 7.63-7.73 (m, 3 H), 7.42 (dd, J = 8.3, 4.8 Hz, 1 H), 6.78 (br. s., 1 H), 6.23 (br. s., 1 H), 3.97-4.06 (m, 2 H), 3.57 (d, J = 6.5 Hz, 2 H), 3.41 (t, J = 11.4 Hz, 2 H), 2.85-2.97 (m, 1 H), 1.92-2.06 (m, 1 H), 1.71 (d, J = 12.0 Hz, 2 H), 1.35-1.51 (m, 2 H), 0.83-0.92 (m, 2 H), 0.58- 0.68 (m, 2 H). A6: 2-chloro-N-cyclopropyl-4-(2- morpholino- 4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₅H₃₀ClN₇O₃ + H]⁺ 512.2 512.7 46 mg (46%); beige solid; free base SMs (method C): 2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.20 mmol), morpholine (0.46 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1 H), 8.03 (s, 1 H), 7.87 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 7.3 Hz, 1 H), 6.53 (s, 1 H), 6.43 (s, 1 H), 3.98-4.08 (m, 2 H), 3.82-3.98 (m, 4 H), 3.75-3.87 (m, 4 H), 3.48-3.59 (m, 2 H), 3.42 (t, J = 10.0 Hz, 2 H), 2.92-3.04 (m, 1 H), 1.93-1.98 (m, 1 H), 1.58-1.77 (m, 2 H), 1.36-1.52 (m, 2 H), 0.75-0.95 (m, 2 H), 0.61-0.73 (m, 2 H). A9: N-cyclopropyl-4-(2-(4- hydroxypiperidin-1-yl)-4-((2- morpholinoethyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₆H₃₄N₈O₃ + H]⁺ 507.3 507.5 25.3 mg (31%); white solid; free base SMs (method C): N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide TFA salt (97 mg, 0.16 mmol), piperidin-4-ol hydrochloride (55 mg, 0.4 mmol), DIPEA (0.14 ml, 0.8 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 6.85-6.78 (m, 1H), 6.32 (s, 1H), 4.54-4.43 (m, 2H), 4.03-3.94 (m, 1H), 3.8-3.65 (m, 6H), 3.48-3.38 (m, 2H), 2.97-2.88 (m, 1H), 2.68 (t, J = 6.0 Hz, 2H), 2.60-2.48 (m, 4H), 2.05-1.94 (m, 2H), 1.65- 1.53 (m, 2H), 0.93-0.83 (m, 2H), 0.66-0.57 (m, 2H). A7: N-cyclopropyl-4-(4-((2- morpholinoethyl)amino)-2- phenoxypyrazolo[1,5-a][1,3,5]triazin- 8-yl)benzamide

[C₂₄H₂₉N₇O₃ + H]⁺ 500.2 500.5 25.4 mg (32%); yellow solid; free base SMs (method E): N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide TFA salt (97 mg, 0.16 mmol), phenol (38 mg, 0.4 mmol), DBU (0.06 ml, 0.4 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.26 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.47-7.41 (m, 2H), 7.32-7.23 (m, 4H), 6.29 (s, 1H), 3.80-3.68 (m, 6H), 2.94-2.87 (m, 1H), 2.69 (t, J = 6.0 Hz, 2H), 2.57-2.49 (m, 4H), 0.90-0.83 (m, 2H), 0.55-0.49 (m, 2H). A8: N-cyclopropyl-4-(4-((2- morpholinoethyl)amino)-2-(pyridin- 3-yloxy)pyrazolo[1,5-a][1,3,5]triazin- 8-yl)benzamide

[C₂₆H₂₈N₈O₃ + H]⁺ 501.2 501.3 22.5 mg (28%); white solid; free base SMs (method E): N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide TFA salt (97 mg, 0.16 mmol), 3-hydroxypyridine (38 mg, 0.2 mmol), DBU (0.06 ml, 0.4 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.67 (d, J = 2.8 Hz, 1H), 8.55 (dd, J = 4.8, 1.2 Hz, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.70-7.65 (m, 3H), 7.41 (dd, J = 8.2, 4.6 Hz, 1H), 7.37-7.33 (m, 1H), 6.33 (s, 1H), 3.80-3.69 (m, 6H), 2.95-2.87 (m, 1H), 2.71 (t, J = 6.0 Hz, 2H), 2.58-2.51 (m, 4H), 0.90- 0.84 (m, 2H), 0.66-0.61 (m, 2H). A12: N-cyclopropyl-4-(2- (methylsulfonyl)-4-((3- morpholinopropyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₈H₃₁N₇O₄ + H]⁺ 530.2 530.3 62 mg (48%); off white solid; TFA salt SMs: (method E)N-cyclopropyl-4-(2-(methylsulfonyl)-4-((3-morpholinopropyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.2 mmol), phenol (75 mg 0.820 mmol), DBU (122 mg, 0.802 mmol), small amount of peroxide carried over from previous step (sulfide → sulfone oxidation). ¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1 H), 7.82 (d, J = 8.5 Hz, 2 H), 7.66 (d, J = 8.5 Hz, 2 H), 7.43- 7.52 (m, 2 H), 7.25-7.35 (m, 3 H), 4.06-4.18 (m, 2 H), 3.93-4.02 (m, 2 H), 3.63-3.85 (m, 8 H), 2.83 (tt, J = 7.4, 3.8 Hz, 1 H), 2.26-2.37 (m, 2 H), 0.77-0.85 (m, 2 H), 0.62-0.68 (m, 2 H). A14: 2-chloro-N-cyclopropyl-4-(4- (((tetrahydro-2H-pyran-4- yl)methyl)amino)-2-((tetrahydro-2H- pyran-4-yl)oxy)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₆H₃₁ClN₆O₄ + H]⁺ 527.2 527.7 69 mg (69%); white solid; free base SMs (method D): 2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.20 mmol), NaH (100 mg, 60% in mineral oil, 2.5 mmol), and tetrahydro-2H-pyran-4-ol (0.044 g, 0.44 mol) ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1 H), 8.14 (s, 1 H), 7.79 (s, 2 H), 6.63 (t, J = 6.1 Hz, 1 H), 6.50 (br. s., 1 H), 5.27-5.33 (m, 1 H), 4.09 (dt, J = 11.6, 3.9 Hz, 2 H), 4.02 (dd, J = 11, 3.9 Hz, 2 H), 3.59- 3.67 (m, 4 H), 3.42 (t, J = 10.3 Hz, 2 H), 2.93-2.99 (m, 1 H), 2.21-2.25 (m, 2 H), 1.91-2.02 (m, 3 H), 1.74 (d, J = 11.8 Hz, 2 H), 1.40-1.50 (m, 2 H), 0.91 (q, J = 7.1 Hz 2 H), 0.68 (q, J = 8.0 Hz, 2 H). A15: 4-(2-(cyclopentylamino)-4- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)-N- cyclopropylbenzamide

[C₂₆H₃₃N₇O₂ + H]⁺ 476.3 476.5 45 mg (45%); white solid; free base SMs (method C): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.21 mmol), cyclopentylamine (0.046 g, 0.47 mol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1 H), 8.05 (br. s., 2 H), 7.77 (d, J = 8.3 Hz, 2 H), 6.41 (br. s., 1 H), 6.28 (br. s., 1 H), 5.11 (br. s., 1 H), 4.30-4.42 (m, 1 H), 4.01 (dd, J = 11.5, 3.0 Hz, 2 H), 3.29-3.56 (m, 4 H), 2.87-2.96 (m, 1 H), 2.02-2.22 (m, 2 H), 1.87-2.00 (m, 1 H), 1.62-1.83 (m, 6 H), 1.49-1.61 (m, 2 H), 1.35-1.48 (m, 2 H), 0.84-0.91 (m, 2 H), 0.58-0.67 (m, 2 H).

The following exemplary compounds were synthesized according to General Methods C, D, E or F, as indicated:

Example number MS calcd; MS ESI [M + H]⁺; Structure HPLC purity ¹H NMR

C2 [C₂₇H₃₀N₆O₃ + H]⁺ 487.2; 487.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.26 (s, 1 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H), 7.45 (t, J = 8.0 Hz, 2 H), 7.25-7.35 (m, 3 H), 5.92 (d, J = 7.5 Hz, 1 H), 4.30 (dq, J = 13.7, 6.8 Hz, 1 H), 4.01 (dd, J = 11.3, 3.5 Hz, 2 H), 3.54 (d, J = 7.0 Hz, 2 H), 3.39 (t, J = 11.0 Hz, 2 H), 1.90-2.04 (m, 1 H), 1.69 (d, J = 12.0 Hz, 2 H), 1.33-1.48 (m, 2 H), 1.27 (d, J = 6.5 Hz, 6 H).

C3 [C₂₇H₃₀N₆O₃ + H]⁺ 487.2; 487.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.29 (s, 1 H), 7.85 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.51 (t, J = 8.0 Hz, 2 H), 7.31-7.41 (m, 3 H), 6.78 (br. s, 1 H), 4.09 (m, J = 7.3 Hz, 2 H), 3.61 (d, J = 6.8 Hz, 2 H), 3.47 (t, J = 11.4 Hz, 2 H), 2.53-2.64 (m, 1 H), 2.05 (br. s., 1 H), 1.77 (d, J = 12.8 Hz, 2 H), 1.41- 1.55 (m, 2 H), 1.34 (d, J = 6.8 Hz, 6 H).

C4 [C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.6; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 8.03 (d, J = 8.3 Hz, 2 H), 7.79 (d, J = 8.3 Hz, 2 H), 6.61-6.68 (m, 1 H), 6.05 (d, J = 7.5 Hz, 1 H), 5.47-5.55 (m, 1 H), 5.11 (br. s, 1 H), 4.24-4.38 (m, 1 H), 4.01 (dd, J = 11.4, 3.4 Hz, 2 H), 3.57 (t, J = 6.5 Hz, 2 H), 3.40 (t, J = 10.9 Hz, 2 H), 2.04-2.14 (m, 2 H), 1.92-2.01 (m, 2 H), 1.78-1.90 (m, 2 H), 1.60-1.76 (m, 4 H), 1.36-1.49 (m, 2 H), 1.22-1.32 (m, 6 H).

C5 [C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.6; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 9.17 (br. s, 1 H), 8.16 (s, 1 H), 7.83 (d, J = 8.3 Hz, 2 H), 7.56 (d, J = 8.5 Hz, 2 H), 7.50 (s, 1 H), 6.93-7.04 (m, 1 H), 5.45-5.58 (m, 1 H), 4.05 (dd, J = 11.5, 3.5 Hz, 2 H), 3.59 (t, J = 6.5 Hz, 2 H), 3.44 (t, J = 11.3 Hz, 2 H), 2.52-2.65 (m, 1 H), 1.58-2.12 (m, 10 H), 1.38-1.53 (m, 2 H), 1.22-1.32 (m, 6 H).

C6 [C₂₄H₂₄N₆O₃ + H]⁺ 445.2; 445.4; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.25 (s, 1 H), 7.82 (d, J = 8.3 Hz, 2 H), 7.64 (d, J = 8.0 Hz, 2 H), 7.39-7.51 (m, 2 H), 7.25-7.36 (m, 3 H), 7.06 (br. s., 1 H), 6.23 (br. s., 1 H), 3.85 (q, J = 5.4 Hz, 2 H), 3.66 (t, J = 4.8 Hz, 2 H), 3.44 (s, 3 H), 2.81-2.99 (m, 1 H), 0.78-0.98 (m, 2 H), 0.53-0.72 (m, 2 H).

C7 [C₂₇H₂₇FN₆O₃ + H]+ 503.2; 503.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 8.03 (t, J = 8.4 Hz, 1 H), 7.54-7.68 (m, 2 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.23-7.35 (m, 3 H), 6.82 (d, J = 12.5 Hz, 1 H), 4.00 (d, J = 8.3 Hz, 2 H), 3.55 (d, J = 6.5 Hz, 2 H), 3.39 (t, J = 11.5 Hz, 2 H), 2.94 (br. d, J = 3.0 Hz, 1 H), 1.98 (br. s., 1 H), 1.68 (d, J = 11.5 Hz, 2 H), 1.33- 1.48 (m, 2 H), 0.80-0.92 (m, 2 H), 0.57-0.67 (m, 2 H).

C8 [C₂₃H₂₈N₆O₃ + H]+ 437.2; 437.2; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.13 (s, 1 H), 7.93 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.05-7.15 (m, 1 H), 6.66 (br. s., 1 H), 5.46-5.51 (m, 1 H), 3.84 (q, J = 5.2 Hz, 2 H), 3.63-3.71 (m, 2 H), 3.42 (s, 3H), 2.94 (m, J = 6.9, 3.4 Hz, 1 H), 2.02-2.14 (m, 2 H), 1.91-2.00 (m, 2 H), 1.79-1.90 (2 H, m), 1.58-1.72 (m, 2 H), 0.83-0.95 (m, 2 H), 0.64- 0.74 (m, 2 H).

C9 [C₂₇H₂₈ClN₇O₂ + H]⁺ 445.2; 445.4; 96.4% at 254 nm (400 MHz, CDCl₃) δ ppm 8.27 (s, 1 H), 8.17 (s, 1 H), 7.81 (s, 2 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.42 (t, J = 7.9 Hz, 2 H), 7.13 (t, J = 1.0 Hz, 1 H), 7.06 (s, 1 H), 6.55 (br. s., 2 H), 4.04 (d, J = 7.3 Hz, 2 H), 3.55 (t, J = 6.8 Hz, 2 H), 3.43 (t, J = 11.7 Hz, 2 H), 2.92- 3.00 (m, 1 H), 1.91-2.13 (m, 1 H), 1.74 (d, J = 12.3 Hz, 2 H), 1.36-1.53 (m, 2 H), 0.91 (s, 2 H), 0.62- 0.80 (m, 2 H).

C10 [C₂₈H₃₁N₇O₂ + H]⁺ 498.6; 498.5; 98.5% at 254 nm (400 MHz, CDCl₃) δ 8.17 (s, 1 H), 8.00 (s, 1 H), 7.79 (d, J = 8.3 Hz, 2 H), 7.74 (d, J = 7.5 Hz, 1 H), 7.34-7.44 (m, 3 H), 7.11 (t, J = 7.4 Hz, 1 H), 7.02 (s, 1 H), 6.54 (t, J = 6.0 Hz, 1 H), 5.90 (br. s., 1 H), 4.04 (dd, J = 11.3, 3.8 Hz, 2 H), 3.54 (t, J = 6.7 Hz, 2 H), 3.43 (t, J = 11.0 Hz, 2 H), 2.88-2.99 (m, 1 H), 2.56 (s, 3 H), 1.93-2.10 (m, 1 H), 1.76 (d, J = 10.5 Hz, 2 H), 1.38-1.53 (m, 2 H), 0.84-0.96 (m, 2 H), 0.58- 0.68 (m, 2 H).

C11 [C₂₆H₃₂FN₇O₂ + H]⁺ 494.3; 494.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 14.23 (br. s., 1 H), 9.86 (br. s., 1 H), 7.91-8.32 (m, 2 H), 7.30-7.79 (m, 3 H), 6.87 (br. s., 1 H), 4.38 (br. s, 1 H), 3.94-4.16 (m, 2 H), 3.54-3.81 (m, 2 H), 3.30-3.54 (m, 2 H), 2.87-3.05 (m, 1 H), 1.39-2.20 (m, 12 H), 0.76- 0.96 (m, 2 H), 0.55-0.73 (m, 2 H).

C12 [C₂₈H₂₉FN₆O₄ + H]⁺ 533.2; 533.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 8.03 (t, J = 8.4 Hz, 1 H), 7.56-7.70 (m, 2 H), 7.34 (t, J = 8.8 Hz, 1 H), 6.79-6.93 (m, 5 H), 5.94 (br. s., 1 H), 4.00 (dd, J = 11.3, 3.3 Hz, 2 H), 3.83 (s, 3 H), 3.54 (t, J = 6.5 Hz, 2 H), 3.39 (t, J = 11.3 Hz, 2 H), 2.88-2.98 (m, 1 H), 1.89-2.04 (m, 1 H), 1.68 (d, J = 11.5 Hz, 2 H), 1.33-1.48 (m, 2 H), 0.82-0.92 (m, 2 H), 0.58- 0.67 (m, 2 H).

C13 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; 96.8% at 254 nm (400 MHz, CDCl₃) δ ppm 8.18 (s, 1 H), 7.72-7.89 (m, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.61 (t, J = 6.0 Hz, 1 H), 6.00 (br. s., 1 H), 5.39-5.56 (m, 1 H), 4.01 (dd, J = 11.3, 3.5 Hz, 2 H), 3.57 (t, J = 6.5 Hz, 2 H), 3.30-3.45 (m, 2 H), 2.83-2.98 (m, 1 H), 2.51 (s, 3 H), 2.03-2.18 (m, 2 H), 1.92-2.00 (m, 2 H), 1.60- 1.90 (m, 6 H), 1.34-1.51 (m, 2 H), 0.81-0.93 (m, 2 H), 0.54-0.68 (m, 2 H).

C14 [C₂₈H₂₈F₂N₆O₃ + H]⁺ 535.2; 535.5; 95.4% at 254 nm (400 MHz, CDCl₃) δ ppm 8.21 (s, 1 H), 7.63 (s, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 7.05-7.20 (m, 2 H), 5.96 (br. s., 1 H), 4.00 (dd, J = 11.2, 3.4 Hz, 2 H), 3.53 (d, J = 7.0 Hz, 2 H), 3.39 (t, J = 11.2 Hz, 2 H), 2.79-2.96 (m, 1 H), 2.36 (s, 3 H), 1.89-2.06 (m, 1 H), 1.68 (d, J = 11.5 Hz, 2 H), 1.30-1.47 (m, 2 H), 0.73-0.95 (m, 2 H), 0.49- 0.68 (m, 2 H).

C15 [C₂₈H₃₆FN₇O₂ + H]⁺ 522.3; 522.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 10.67 (br. s., 1 H), 8.02- 8.15 (m, 2 H), 7.82-7.93 (m, 1 H), 7.71 (d, J = 8.3 Hz, 1 H), 7.04 (d, J = 13.3 Hz, 1 H), 6.81 (br. s., 1 H), 4.54-4.67 (m, 1 H), 4.05 (dd, J = 11.5, 3.0 Hz, 2 H), 3.52 (t, J = 6.5 Hz, 2 H), 3.43 (t, J = 10.9 Hz, 2 H), 3.14 (s, 3 H), 2.92-3.01 (m, 1 H), 1.96-2.08 (m, 1 H), 1.92 (d, J = 12.3 Hz, 2 H), 1.69-1.87 (m, 5 H), 1.39-1.61 (m, 6 H), 1.13-1.31 (m, 1 H), 0.84- 0.95 (m, 2 H), 0.62-0.72 (m, 2 H).

C16 [C₂₆H₃₂ClN₇O₂ + H]⁺ 510.2; 510.2; 97.0% at 254 nm (400 MHz, CDCl₃) δ ppm 8.06 (d, J = 9.0 Hz, 2 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.3 Hz, 1 H), 6.53 (br. s., 1 H), 6.36 (br. s., 1 H), 4.02 (d, J = 8.5 Hz, 2 H), 3.88 (br. s., 4 H), 3.51 (t, J = 6.5 Hz, 2 H), 3.41 (t, J = 11.7 Hz, 2 H), 2.85-3.03 (m, 1 H), 1.87- 2.04 (m, 1 H), 1.55-1.79 (m, 8 H), 1.36-1.52 (m, 2 H), 0.81-0.97 (m, 2 H), 0.60-0.73 (m, 2 H).

C17 [C₂₈H₃₀N₆O₃ +H]⁺ 499.2; 499.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.20 (s, 1 H), 7.64-7.86 (m, 2 H), 7.50-7.60 (m, 1 H), 7.40-7.49 (m, 2 H), 7.24-7.36 (m, 3 H), 7.17 (br. s., 1 H), 6.72-6.82 (m, 1 H), 4.02 (dd, J = 11.3, 3.5 Hz, 2 H), 3.56 (t, J = 6.5 Hz, 2 H), 3.32-3.45 (m, 2 H), 2.20 (s, 3 H), 1.91-2.05 (m, 1 H), 1.71 (d, J = 12.5 Hz, 2 H), 1.53 (br. s., 1 H), 1.34-1.48 (m, 2 H), 1.02-1.18 (m, 2 H), 0.66-0.93 (m, 2 H).

C18 [C₂₇H₃₅N₇O₂ + H]⁺ 490.3; 490.5; 95% at 254 nm (400 MHz, MeOD-d₄) δ ppm 8.14 (br. s., 1 H), 7.23- 7.51 (m, 3 H), 4.41 (br. s., 1 H), 3.97 (d, J = 8.5 Hz, 2 H), 3.55 (d, J = 6.5 Hz, 2 H), 3.41 (t, J = 11.7 Hz, 2 H), 2.31 (s, 3 H), 2.00-2.16 (m, 3 H), 1.57-1.94 (m, 9 H), 1.31-1.48 (m, 2 H), 0.80-1.03 (m, 4 H).

C19 [C₃₀H₃₃N₇O₄ + H]⁺ 556.3; 556.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.25 (s, 1 H), 8.14 (s, 1 H), 7.61 (s, 2 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.33- 7.40 (m, 1 H), 7.25-7.33 (m, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 7.8 Hz, 1 H), 6.84 (t, J = 6.1 Hz, 1 H), 6.22 (d, J = 3.0 Hz, 1 H), 3.97 (dd, J = 11.4, 3.1 Hz, 2 H), 3.44-3.54 (m, 2 H), 3.37 (t, J = 11.3 Hz, 2 H), 2.79-2.92 (m, 1 H), 2.31 (s, 3 H), 2.10 (s, 3 H), 1.94 (s, 1 H), 1.66 (d, J = 11.5 Hz, 2 H), 1.27-1.44 (m, 2 H), 0.76-0.88 (m, 2 H), 0.54-0.65 (m, 2 H).

C20 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.5; 99.1% at 254 nm (400 MHz, CDCl₃) δ ppm 8.21 (s, 1 H), 7.64 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.15-7.38 (m, 5 H), 6.82 (t, J = 6.1 Hz, 1 H), 5.93 (br. s., 1 H), 4.00 (dd, J = 11.5, 3.5 Hz, 2 H), 3.53 (t, J = 6.5 Hz, 2 H), 3.39 (t, J = 11.0 Hz, 2 H), 2.80-2.97 (m, 1 H), 2.34 (s, 3 H), 1.88-2.06 (m, 1 H), 1.68 (d, J = 13.1 Hz, 2 H), 1.31-1.49 (m, 2 H), 0.77-0.96 (m, 2 H), 0.49- 0.67 (m, 2 H).

C21 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.5; 98.2% at 254 nm (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 7.68 (s, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.40 (td, J = 8.3, 6.5 Hz, 1 H), 7.23-7.31 (m, 1 H), 7.07-7.15 (m, 2 H), 7.01 (t, J = 8.2 Hz, 1 H), 6.81 (t, J = 6.1 Hz, 1 H), 5.94 (d, J = 2.3 Hz, 1 H),4.01 (dd, J = 11.3, 3.3 Hz, 2 H), 3.55 (t, J = 6.7 Hz, 2 H), 3.40 (td, J = 11.7, 1.6 Hz, 2 H), 2.83-2.94 (m, 1 H), 2.38 (s, 3 H), 1.93-2.07 (m, 1 H), 1.65-1.73 (m, 2 H), 1.33-1.50 (m, 2 H), 0.80- 0.95 (m, 2 H), 0.50-0.68 (m, 2 H).

C22 [C₂₈H₃₇N₇O₂ + H]⁺ 504.3; 504.6; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 13.88 (br. s., 1 H), 9.82 (br. s., 1 H), 7.79-8.20 (m, 1 H), 7.50 (br. s., 3 H), 5.92-6.25 (m, 1 H), 4.02 (br. s., 3 H), 3.63 (br. s., 2 H), 3.30-3.52 (m, 2 H), 2.81-3.01 (m, 1 H), 2.55 (br. s., 3 H), 1.29-2.18 (m, 15 H), 0.80-0.97 (m, 2 H), 0.49-0.74 (m, 2 H).

C23 [C₂₇H₃₅N₇O₃ + H]⁺ 506.3; 506.5; 97.4% at 254 nm (400 MHz, CDCl₃) δ ppm 10.33 (br. s., 1 H), 8.00 (br. s., 1 H), 7.31-7.47 (m, 2 H), 7.16 (br. s., 1 H), 5.95 (br. s., 1 H), 4.13 (br. s., 1 H), 4.05 (d, J = 11.3 Hz, 4 H), 3.29-3.70 (m, 8 H), 2.85-2.98 (m, 1 H), 2.49 (s, 3 H), 1.79-2.07 (m, 4 H), 1.73 (d, J = 10.3 Hz, 2 H), 1.37-1.55 (m, 2 H), 0.80-0.96 (m, 2 H), 0.53-0.68 (m, 2 H).

C24 [C₂₉H₃₁FN₆O₃ + H]⁺ 531.2; 531.2; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.34 (s, 1 H), 7.77 (s, 1 H), 7.62 (dd, J = 8.03, 1.25 Hz, 1 H), 7.46 (td, J = 8.34, 6.65 Hz, 1 H), 7.24 (d, J = 8.03 Hz, 1 H), 7.09-7.18 (m, 2 H), 7.05 (tdd, J = 8.50, 8.50, 2.50, 0.80 Hz, 1 H), 3.90 (br. s., 1 H), 3.41 (d, J = 7.03 Hz, 2 H), 2.85 (tt, J = 7.37, 3.80 Hz, 1 H), 2.33 (s, 3 H), 1.69-1.84 (m, 3 H), 1.42-1.60 (m, 6 H), 0.77- 0.84 (m, 2 H), 0.59-0.65 (m, 2 H).

C25 [C₂₉H₃₁FN₆O₄ + H]⁺ 547.2; 547.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.25-7.31 (m, 2 H), 7.22 (t, J = 8.8 Hz, 1 H), 6.70-6.84 (m, 3 H), 5.87 (br. s., 1 H), 4.01 (dd, J = 11.2, 3.4 Hz, 2 H), 3.84 (s, 3 H), 3.56 (t, J = 6.5 Hz, 2 H), 3.34-3.45 (m, 2 H), 2.89 (s, 1 H), 2.37 (s, 3 H), 1.93-2.04 (m, 1 H), 1.70 (d, J = 11.3 Hz, 2 H), 1.35-1.49 (m, 2 H), 0.83- 0.91 (m, 2 H), 0.54-0.65 (m, 2 H).

C26 [C₂₈H₂₉F₂N₇O₃ + H]+ 550.2; 550.3; 98.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.46 (s, 1 H), 7.72 (s, 1 H), 7.54-7.63 (m, 1 H), 7.29-7.38 (m, 2 H), 7.17- 7.29 (m, 2 H), 4.08-4.21 (m, 2 H), 4.05 (t, J = 5.65 Hz, 2 H), 3.70-3.91 (m, 4 H), 3.55 (t, J = 5.52 Hz, 2 H), 3.15-3.30 (m, 2 H), 2.78-2.88 (m, 1 H), 2.29 (s, 3 H), 0.76-0.85 (m, 2 H), 0.56-0.64 (m, 2 H).

C27 [C₂₈H₃₀FN₇O₃ + H]⁺ 532.2; 532.3; 99.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.45 (s, 1 H), 7.80 (s, 1 H), 7.64 (dd, J = 8.00, 1.80 Hz, 1 H), 7.48-7.56 (m, 1 H), 7.25 (d, J = 8.03 Hz, 1 H), 7.09-7.22 (m, 3 H), 4.04-4.20 (m, 2 H), 4.01 (t, J = 5.50 Hz, 2 H), 3.67- 3.89 (m, 4 H), 3.53 (t, J = 5.50 Hz, 2 H), 3.12-3.29 (m, 2 H), 3.00 (s, 1 H), 2.81-2.89 (m, 1 H), 2.32 (s, 3 H), 0.77-0.85 (m, 2 H), 0.57-0.65 (m, 2 H).

Example B1. Synthesis of tert-butyl tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (1.51 g, 3 mmol) and N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzam-ide (2.71 g, 3 equiv) in THF (12 mL) was N added 2 M K₃PO₄ (3 mL, 6 mmol, 2 equiv), followed by PdCl₂dppfDCM (122 mg, 0.15 mmol, 5 mol %). The resulting mixture was purged with Ar, and then microwaved 2 h at 120° C. After repeating the reaction on the same scale, both reactions were combined, diluted with H₂O (30 mL) and extracted with EtOAc (30 mL×2). It was concentrated and purified by purified by flash chromatography (EtOAc/hex 0-60%) to give the intermediate as light yellow foam.

The above light yellow foam was redissolved in DCM (20 mL) and treated with TFA (4 mL). After stirring O/N, it was concentrated to dryness and purified by flash chromatography (gradient: EtOAc/hex 0-100%) and triturated with MeOH to give the title compound (1.819 g, 61% over 2 steps) as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 1H), 7.77 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.32-7.27 (m, 3H), 7.24 (d, J=8.0 Hz, 1H), 6.39 (t, J=6.2 Hz, 1H), 5.84-5.82 (m, 1H), 5.69 (s, 1H), 4.05 (dd, J=11.6, 3.2 Hz, 2H), 3.44 (dt, J=12.0, 1.6 Hz, 2H), 3.32 (t, J=6.4 Hz, 2H), 2.92-2.76 (m, 1H), 2.34 (s, 1H), 2.09-1.97 (m, 1H), 1.82-1.75 (m, 2H), 1.53-1.40 (m, 2H), 0.90-0.84 (m, 2H), 0.63-0.58 (m, 1H); MS ESI [M+H]⁺ 498.5, calcd for [C₂₉H₃₁N₅O₃+H]⁺ 498.2.

The following final compounds were synthesized according to the synthesis of Example B1

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Salt form B2: N-cyclopropyl-4-(7-((2- methoxyethyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₂₅H₂₅N₅O₃ + H]⁺ 444.2; 444.4 308 mg (70%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate (464 mg, 1 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (335 mg, 1.2 mmol), PdCl₂dPPf•DCM (82 mg, 0.1 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.29 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.32-7.26 (m, 3H), 6.59 (t, J = 5.2 Hz, 1H), 6.18 (br, s, 1H), 5.68 (s, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.57 (q, J = 5.3 Hz, 2H), 3.45 (s, 3H), 2.95-2.87 (m, 1H), 0.90-0.85 (m, 2H), 0.66-0.60 (m, 2H). B3: N-cyclopropyl-4-(5-phenoxy-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₉N₅O₃ + H]⁺ 484.2; 484.5 152 mg (52%, 2 steps); off white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)meth- yl)carbamate (302 mg, 0.6 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (207 mg, 0.72 mmol), PdCl₂dPPf•DCM (49 mg, 0.06 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.33-7.26 (m, 3H), 6.41 (t, J = 5.8 Hz, 1H), 6.19 (br, s, 1H), 5.68 (s, 1H), 4.08-4.02 (m, 214), 3.40 (t, J = 11.2 Hz, 2H), 3.31 (t, J = 6.4 Hz, 2H), 2.95-2.87 (m, 1H), 2.09-1.97 (m, 1H), 1.81-1.73 (m, 2H), 1.52-1.40 (m, 2H), 0.91-0.85 (m, 2H), 0.66-0.60 (m, 2H). B4: N-cyclopropyl-4-(7-((2- methoxyethyl)amino)-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₂₄H₂₄N₆O₃ + H]⁺ 445.2; 445.6 133 mg (43%, 2 steps); beige solid; TFA salt SMs: tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carb- amate (261 mg, 0.56 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz- amide (178 mg, 0.62 mmol), PdCl₂dppf•DCM (46 mg, 0.056 mmol, 10 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.91 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 9.2 Hz, 1H), 8.37-8.32 (m, 2H), 7.96 (dd, J = 8.6, 5.4 Hz, 1H), 7.76 (d, 3 = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 5.98 (s, 1H), 3.72 (t, J = 5.0 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.44 (s, 3H), 2.88-2.81 (m, 1H), 0.85-0.78 (m, 2H), 0.67-0.62 (m, 2H). B5: N-cyclopropyl-2-methyl-4-(7-((2- morpholinoethyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.6 2.943 g (68%, 2 steps); light pink solid; TFA salt SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (1.80 g, 3.47 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz- amide (3.14 g, 10.42 mmol), PdCl₂dppf•DCM (142 mg, 0.174 mmol, 5 mol %)-identical two reactions on the same scale; TFA (6 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.31 (s, 1H), 7.78 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48-7.42 (m, 2H), 7.30-7.23 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 5.90 (s, 1H), 4.10-3.70 (m, 6H), 3.70-3.10 (m, 6H), 2.87-2.79 (m, 1H), 2.24 (s, 3H), 0.83-0.77 (m, 2H), 0.63-0.58 (m, 2H). B6: N-cyclopropyl-4-(7-((2- morpholinoethyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₂₈H₃₀N6O₃ + H]⁺ 499.2; 499.5 56 mg (13%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (0.35 g, 0.68 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (215 mg, 0.75 mmol), PdCl₂dppf•DCM (55 mg, 0.07 mmol, 10 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (s, 1 H), 7.88 (d, 3 = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.50-7.36 (m, 2H), 7.33-7.21 (m, 3H), 6.90 (t, J = 4.5 Hz, 1H), 6.33 (br, s, 1H), 5.60 (s, 1H), 3.79 (t, J = 4.5 Hz, 4H), 3.44 (q, J = 5.7 Hz, 2H), 2.89 (tq, J = 7.0, 3.5 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.60 (br, s, 4H), 0.89-0.81 (m, 2H), 0.65-0.57 (m, 2H). B7: 2-chloro-N-cyclopropyl-4-(5- phenoxy-7-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₈ClN₅O₃ + H]⁺ 518.2; 518.7 141 mg (54%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)meth- yl)carbamate (252 g, 0.5 mmol), (3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (132 g, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 1H), 7.96 (s, 1H), 7.73-7.66 (m, 2H), 7.48 (t, J = 7.8 Hz, 2H), 7.32-7.26 (m, 3H), 6.49 (br, s, 1H), 6.40 (t, J = 6.2 Hz, 1H), 5.72 (s, 1H), 4.09-4.02 (m, 2H), 3.44 (t, J = 11.6 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 2.97-2.89 (m, 1H), 2.10-1.97 (m, 1H), 1.82-1.75 (m, 2H), 1.53-1.41 (m, 2H), 0.91-0.85 (m, 2H), 0.68-0.62 (m, 2H). B8: N-cyclopropyl-2-fluoro-4-(5- phenoxy-7-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₈FN₅O₃ + H]⁺ 502.2; 502.5 173 mg (69%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)meth- yl)carbamate (252 g, 0.5 mmol), (4-(cyclopropylcarbamoyl)-3-fluorophenyl)boronic acid (123 g, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s, 1H), 8.01 (t, J = 8.4 Hz, 1 H), 7.69 (d, J = 14.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.35-7.26 (m, 3H), 6.85-6.78 (m, 1H), 6.42 (t, J = 6.0 Hz, 1H), 5.72 (s, 1H), 4.09-4.02 (m, 2H), 3.44 (t, J = 11.8 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 2.98- 2.90 (m, 1 H), 2.10-1.98 (m, 1H), 1.81-1.75 (m, 2H), 1.53-1.41 (m, 2H), 0.91-0.85 (m, 2H), 0.67-0.60 (m, 2H). B9: N-cyclopropyl-2-methyl-4-(5- (pyridin-3-yloxy)-7-(((tetrahydro- 2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₃₀N₆O₃ + H]⁺ 499.2; 499.2 118 mg (39%, 2 steps); brown solid; TFA salt SMs: tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran- 4-yl)methyl)carbamate (232 mg, 0.5 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.98 (d, J = 2.5 Hz, 1H), 8.67 (d, J = 5.3 Hz, 1H), 8.26 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 7.9, 5.4 Hz, 1H), 7.59-7.51 (m, 2H), 7.29 (s, 1H), 6.61 (t, J = 6.4 Hz, 1H), 6.18 (br, s, 1H), 5.78 (s, 1H), 4.07 (dd, J = 11.0,4.0 Hz, 2H), 3.46 (t, J = 11.4 Hz, 2H), 3.38 (t, J = 6.5 Hz, 2H), 2.96-2.86 (m, 1H), 2.39 (s, 3H), 2.13-2.00 (m, 1 H), 1.85-1.76 (m, 2H), 1.50 (qd, J = 12.2, 4.1 Hz, 2H), 0.88 (q, J = 6.3 Hz, 2H), 0.69-0.60 (m, 2H). B10: N-cyclopropyl-4-(5-((2-hydroxy-2- methylpropyl)amino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.3 98 mg (32%, 2 steps); light brown solid; TFA salt SMs: tert-butyl (3-bromo-5-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (249 mg, 0.5 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (br, s, 1 H), 7.94 (br, s, 1H), 7.44-7.19 (m, 4H), 6.90 (br, s, 1H), 6.26 (br, s, 1H), 5.37 (br, s, 1H), 4.04 (d, J = 8.8 Hz, 2H), 3.56-3.24 (m, 6H), 3.00-2.86 (m, 1 H), 2.45 (s, 3 H), 2.10-1.96 (m, 1 H), 1.73-1.68 (m, 2 H), 1.55-1.41 (m, 2 H), 1.34 (s, 6H), 0.96-0.78 (m, 2 H), 0.72-0.57 (m, 2 H). B11: N-cyclopropyl-2-methyl-4-(5- morpholino-7-(((tetrahydro-2H- pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2 68 mg (22%, 2 steps); brown solid; TFA salt SMs: tert-butyl (3-bromo-5-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate (248 mg, 0.5 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.18 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.28 (t, J = 6.3 Hz, 1H), 5.97 (br, s, 1H), 5.35 (s, 1H), 4.05 (dd, J = 12.0, 3.5 Hz, 2H), 3.91-3.82 (m, 4H), 3.74-3.67 (m, 4H), 3.49-3.38 (m, 2H), 3.26 (t, J = 6.3 Hz, 2H), 2.97-2.88 (m, 1H), 2.52 (s, 3 H), 2.06-1.92 (m, 1H), 1.79 (d, J = 12.8 Hz, 2H), 1.53-1.39 (m, 2H), 0.93-0.84 (m, 2H), 0.67-0.58 (m, 2H). B12: N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-(((tetrahydro-2H- pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₀FN₅O₃ + H]⁺ 516.2; 516.5 130 mg (50%, 2 steps); off white solid; free base SMs: tert-butyl (3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran- 4-yl)methyl)carbamate (261 mg, 0.5 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24 (s, 1H), 7.78 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 15.0, 7.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 2H), 7.05-6.97 (m, 1H), 6.43 (t, J = 6.4 Hz, 1H), 5.83 (br, s, 1H), 5.69 (s, 1H), 4.09-4.02 (m, 2H), 3.44 (t, J = 12.0 Hz, 2H), 3.33 (t, J = 6.6 Hz, 2H), 2.93-2.86 (m, 1H), 2.37 (s, 3H), 2.10-1.98 (m, 1H), 1.82-1.75 (m, 2H), 1.53-1.42 (m, 2H), 0.91-0.85 (m, 2H), 0.63-0.58 (m, 2H). B13: N-cyclopropyl-4-(7-((2- methoxyethyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3- yl)-2-methylbenzamide

[C₂₆H₂₇N₅O₃ + H]⁺ 458.2; 458.4 81 mg (35%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate (232 mg, 0.5 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s, 1H), 7.78 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.32-7.26 (m, 4H), 7.24 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 5.4 Hz, 1H), 5.81 (br, s, 1H), 5.70 (s, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 3.45 (s, 3H), 2.92-2.87 (m, 1H), 2.35 (s, 3H), 0.90-0.85 (m, 2H), 0.63-0.57 (m, 2H). B14: 4-(5-(cyclopentylamino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.5 93 mg (38%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate (200 mg, 0.41 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (365 mg, 1.21 mmol), PdCl₂dppf•DCM (33 mg, 0.040 mmol); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.93 (br, s, 1H), 7.89 (s, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26-7.16 (m, 2 H), 7.03 (t, J = 5.6 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 5.11 (s, 1H), 4.05 (dd, J = 11.4, 3.6 Hz, 2H), 3.89 (br, s, 1H), 3.44 (t, J = 11.4 Hz, 2H), 3.35 (t, J = 6.3 Hz, 2H), 2.93-2.91 (m, 1H), 2.42 (s, 3 H), 2.04 (m, 3H), 1.89-1.60 (m, 8H), 1.54-1.37 (m, 2H), 0.95-0.78 (m, 2H), 0.72-0.58 (m, 2H). B15: N-(4-(5-(cyclopentylamino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylphenyl)cyclopropane carboxamide

[C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.5 37 mg (14%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate (220 mg, 0.44 mmol), N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (200 mg, 0.66 mmol), PdCl₂dppf•DCM (36 mg, 0.044 mmol); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.29 (br, s, 1H), 8.92 (br, s, 1H), 7.90 (br, s, 1H), 7.76 (br, s, 1H), 7.50 (br, s, 1H), 7.33 (br, s, 2H), 7.22 (br, s, 1H), 6.97 (br, s, 1H), 5.11 (s, 1H), 4.07 (dd, J = 11.4, 3.6 Hz, 2H), 3.89 (t, J = 5.5 Hz, 1H), 3.46 (t, J = 11.5 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 2.31 (br, s, 3H), 2.13-1.95 (m, 3), 1.90-1.59 (m, 8H), 1.55-1.39 (m, 2H), 1.11 (br, s, 2H), 0.96-0.78 (m, 2H). B16: N-(2-methyl-4-(7-(((tetrahydro-2H- pyran-4-yl)methyl)amino)-5- ((tetrahydro-2H-pyran-4- yl)oxy)pyrazolo[1,5-a]pyrimidin-3- yl)phenyl)cyclopropanecarboxamide

[C₂₈H₃₅N₅O₄ + H]⁺ 506.3; 506.5 56 mg (36%, 2 steps); white solid; free base SMs: tert-butyl(3-bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetra- hydro-2H-pyran-4-yl)methyl)carbamate (160 mg, 0.31 mmol), N-(2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (110 mg, 0.37 mmol), PdCl₂dppf•DCM (25 mg, 0.031 mmol); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s, 1H), 7.93 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.29 (t, J = 6.1 Hz, 1H), 5.99 (br, s, 1H), 5.47 (s, 1H), 5.43-5.33 (m, 1H), 4.11-3.95 (m, 4H), 3.65 (t, J = 9.5 Hz, 2H), 3.41 (t, J = 11.7 Hz, 2H), 3.26 (t, J = 6.5 Hz, 2H), 2.97-2.84 (m, 1H), 2.51 (s, 3H), 2.27-2.10 (m, 3H), 1.93-1.82 (m, 2H), 1.75 (d, J = 12.3 Hz, 2H), 1.51-1.34 (m, 2H), 0.96-0.79 (m, 2H), 0.67-0.54 (m, 2H). B17: N-(2-methyl-4-(5-((tetrahydro-2H- pyran-4-yl)amino)-7-(((tetrahydro- 2H-pyran-4-yl) methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl) phenyl)cyclopropanecarboxamide

[C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.5 35 mg (23%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetra- hydro-2H-pyran-4-yl)methyl)carbamate (72 mg, 0.18 mmol), N-(2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (66 mg, 0.21 mmol), PdCl₂dppf•DCM (15 mg, 0.018 mmol); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.65 (br. s, 2H), 7.96 (s, 1H), 7.43-7.30 (m, 3H), 6.83 (br, s, 1H), 6.06 (br, s, 1H), 5.08 (s, 1H), 4.13-3.97 (m, 4H), 3.66 (br, s, 1H), 3.54 (t, J = 11.0 Hz, 2H), 3.46 (t, J = 11.0 Hz, 2H), 3.35 (t, J = 6.4 Hz, 2H), 2.99-2.85 (m, 1 H), 2.48 (s, 3H), 2.12-1.95 (m, 3H), 1.93- 1.73 (m, 4H), 1.58-1.42 (m, 2H), 0.94-0.81 (m, 2H), 0.70-0.55 (m, 2H). B18: N-(2-methyl-4-(5-phenoxy-7- ((tetrahydro-2H-pyran-4- yl)methoxy)pyrazolo[1,5- a]pyrimidin-3-yl)phenyl) cyclopropanecarboxamide

[C₂₉H₃₀N₄O₄ + H]⁺ 499.2; 499.5 12 mg (4%, 2 steps); beige solid; free base SMs: 3-bromo-5-phenoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine (241 mg, 0.60 mmol), N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane carboxamide (216 mg, 0.72 mmol), PdCl₂dppf•DCM (49 mg, 0.060 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.33 (br, s, 1 H), 7.74 (br, s, 1 H), 7.62-7.42 (m, 3H), 7.39-7.14 (m, 4H), 5.97 (br, s, 1H), 5.85 (br, s, 1H), 4.22 (d, J = 6.3 Hz, 2H), 4.07 (d, J = 9.3 Hz, 2H), 3.50 (t, J = 11.8 Hz, 2H), 2.89 (br, s, 1H), 2.40 (br, s, 1H), 2.32 (br, s, 3H), 1.90 (d, J = 11.5 Hz, 2H), 1.57- 1.45 (m, 2H), 0.87 (d, J = 6.0 Hz, 2H), 0.60 (br, s, 2H). B19: N-cyclopropyl-2-methyl-4-(7-((3- morpholinopropyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₃₀H₃₄N₆O₃ + H]⁺ 527.3; 527.3 142 mg (72%, 2 steps); pinkish-white solid; TFA salt SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(3-morpholinopropyl)carbamate (200 mg, 0.375 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (124 mg, 1.1 equiv), PdCl₂dppf•DCM (31 mg, 0.0375 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.82 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.35-7.23 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 4.14-4.00 (m, 2H), 3.84-3.71 (m, 2H), 3.63-3.44 (m, 4H), 3.38-3.27 (m, 4H), 3.23-3.09 (m, 2H), 2.88-2.78 (m, 1H), 2.31-2.10 (m, 5H), 0.86-0.74 (m, 2H), 0.65-0.55 (m, 2H). B20: N-cyclopropyl-2-methyl-4-(5- phenoxy-7-((2-(tetrahydro-2H- pyran-4- yl)ethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₃₀H₃₃N₅O₃ + H]⁺ 512.3; 512.2 100 mg (53%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4- yl)ethyl)carbamate (192 mg, 0.371 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (123 mg, 0.409 mmol), PdCl₂dppf•DCM (30 mg, 0.037 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24 (s, 1H), 7.78 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41-7.50 (m, 2H), 7.32-7.28 (m, 3H), 7.24 (d, J = 7.8 Hz, 1H), 6.24 (t, J = 5.8 Hz, 1H), 5.83 (br, s, 1H), 5.67 (s, 1H), 4.00 (dd, J = 11.2, 3.6 Hz, 2H), 3.50-3.36 (m, 4H), 2.96-2.83 (m 1H), 2.34 (s, 3H), 1.76 (t, J = 6.5 Hz, 3H), 1.68 (d, J = 13.8 Hz, 2H), 1.47-1.34 (m, 2H), 0.92-0.82 (m, 2H), 0.60 (br, s, 2H). B21: 4-(5-(cyclopentyloxy)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₈H₃₅N₅O₃ + H]⁺ 490.3; 490.5 70 mg (32%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-(cyclopentyloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate (224 mg, 0.453 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (150 mg, 0.499 mmol), PdCl₂dppf•DCM (37 mg, 0.045 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 7.97 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.24 (t, J = 5.6 Hz, 1H), 5.94 (br, s, 1 H), 5.61-5.51 (m, 1H), 5.44 (s, 1H), 4.03 (dd, J = 11.3, 3.3 Hz, 2H), 3.42 (t, J = 11.0 Hz 2H), 3.25 (t, J = 6.7 Hz, 2H), 2.98-2.85 (m, 1H), 2.54 (s, 3H), 2.16-1.60 (m, 11H), 1.50-1.34 (m, 2H), 0.94-0.83 (m, 2H), 0.63 (br, s, 2H). B22: N-cyclopropyl-2-methyl-4-(5- (pyridin-3-yloxy)-7-((2-(tetrahydro- 2H-pyran-4- yl)ethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.5 92 mg (40%, 2 steps); yellow solid; TFA salt SMs: tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H- pyran-4-yl)ethyl)carbamate (190 mg, 0.367 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (121 mg, 0.403 mmol), PdCl₂dppf•DCM (30 mg, 0.0367 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.81 (br, s, 1H), 8.68-8.62 (m, 1H), 8.38 (s, 1H), 8.27-8.20 (m, 1 H), 7.91-7.84 (m, 1H), 7.72 (s, 1H), 7.64-7.55 (m, 1H), 7.25-7.17 (m, 1H), 5.96 (s, 1H), 4.02-3.91 (m, 2H), 3.54 (t, J = 6.5 Hz, 2H), 3.45 (t, J = 11.3 Hz, 2H), 2.89-2.79 (m, 1H), 2.28 (s, 3H), 1.81- 1.69 (m, 5H), 1.44-1.29 (m, 2H), 0.81 (d, J = 6.3 Hz, 2H), 0.61 (br, s, 2H). HPLC purity: 99.3% at 254 nm. B23: 4-(5-(cyclohexyloxy)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₉H₃₇N₅O₃ + H]⁺ 504.3; 504.5 146 mg (57%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-(cyclohexyloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate (281 mg, 0.553 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (183 mg, 0.608 mmol), PdCl₂dppf•DCM (45 mg, 0.055 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (s, 1 H), 8.01 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.24 (t, J = 6.1 Hz, 1H), 5.93 (br, s, 1H), 5.45 (s, 1H), 5.28-5.12 (m, 1H), 4.03 (dd, J = 11.4, 3.6 Hz, 2H), 3.41 (t, J = 12.0 Hz, 2H), 3.25 (t, J = 6.4 Hz, 2H), 2.92 (td, J = 7.2, 3.8 Hz, 1H), 2.54 (s, 3H), 2.23-2.13 (m, 2H), 2.05-1.92 (m, 1H), 1.91-1.81 (m, 2H), 1.75 (d, J = 13.6 Hz, 2H), 1.70-1.22 (m, 8H), 0.90 (q, J = 6.5 Hz 2H), 0.67-0.59 (m, 2H). HPLC purity: 95.7% at 254 nm. B24: 4-(5-(cyclohexylamino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₉H₃₈N₆O₂ + H]⁺ 503.3; 503.5 61 mg (20%, 2 steps); white solid; TFA salt SMs: (250 mg, 0.493 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (178 mg, 0.692 mmol), PdCl₂dppf•DCM (40 mg, 0.049 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 7.51-7.46 (m, 1H), 7.43 (s, 2H), 4.89 (br, s, 1H), 4.03-3.95 (m, 2H), 3.83-3.72 (m, 1H), 3.51-3.42 (m, 4H), 2.93-2.83 (m, 1H), 2.47 (s, 3H), 2.12-2.01 (m, 3H), 1.87-1.29 (m, 12H), 0.87-0.80 (m, 2H), 0.67-0.60 (m, 2H). HPLC purity: 96.3% at 254 nm. B25: N-cyclopropyl-4-(7-(isobutylamino)- 5-(pyridin-3-yloxy)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₆H₂₈N₆O₂ + H]⁺ 457.2; 457.4 78 mg (51%, 2 steps); yellow solid; TFA salt SMs: tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate (125 mg, 0.27 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (98 mg, 0.32 mmol), PdCl₂dppf•DCM (22 mg, 0.027 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.84 (s, 1H), 8.67 (d, J = 5.3 Hz, 1H), 8.36 (s, 1H), 8.33-8.27 (m, 1H), 7.95-7.88 (m, 1H), 7.68 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.94 (s, 1H), 3.30-3.27 (m, 2H), 2.86-2.78 (m, 1H), 2.27 (s, 3H), 2.14-2.05 (m, 1H), 1.06 (d, J = 6.8 Hz, 6H), 0.83-0.75 (m, 2H), 0.62-0.55 (m, 2H). B26: N-cyclopropyl-4-(7-(isobutylamino)- 5-((tetrahydro-2H-pyran-4- yl)amino)pyrazolo[1,5-a]pyrimidin- 3-yl)-2-methylbenzamide

[C₂₆H₃₄N₆O₂ + H]⁺ 463.3; 463.5 43 mg (36%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(isobutyl)carbamate (100 mg, 0.21 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (76 mg, 0.25 mmol), PdCl₂dppf•DCM (17 mg, 0.021 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.42-7.33 (m, 3H), 6.82 (br, s, 1H), 6.03 (br, s, 1H), 5.07 (s, 1H), 4.09-4.00 (m, 2H), 3.66 (br, s, 1H), 3.58-3.51 (m, 2H), 3.27 (t, I = 6.4 Hz, 2H), 2.94 (s, 1H), 2.49 (s, 3H), 2.16-2.07 (m, 1H), 2.04-1.94 (m, 2H), 1.93-1.80 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.92-0.84 (m, 2H), 0.67-0.60 (m, 2H). B27: N-cyclopropyl-4-(7-((2-hydroxy-2- methylpropyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3- yl)-2-methylbenzamide

[C₂₇H₂₉N₅O₃ + H]⁺ 472.2; 472.4 14 mg (15%, 2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate (115 mg, 0.20 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (72 mg, 0.24 mmol), PdCl₂dppf•DCM (16 mg, 0.02 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s, 1H), 7.75 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2 H), 7.31-7.25 (m, 4H), 7.22 (d, J = 8.3 Hz, 1H), 6.69-6.62 (m, 1H), 5.85 (br, s, 1H), 5.72 (s, 1H), 3.36 (d, J = 6.0 Hz, 2H), 2.89 (br, s, 1H), 2.33 (s, 3H), 1.41 (s, 6H), 0.87 (s, 2H), 0.64-0.55 (m, 2H). B28: N-cyclopropyl-4-(7-((2-hydroxy-2- methylpropyl)amino)-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-3- yl)-2-methylbenzamide

[C₂₆H₂₈N₆O₃ + H]⁺ 473.2; 473.4 42 mg (34%, 2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbon- yl)oxy)-2-methylpropyl)carbamate (120 mg, 0.21 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (75 mg, 0.25 mmol), PdCl₂dppf•DCM (17 mg, 0.02 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.80-8.76 (m, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 8.23- 8.16 (m, 1H), 7.88-7.82 (m, 1H), 7.72 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 3.46 (s, 2H), 2.87-2.79 (m, 1H), 2.27 (s, 3H), 1.35 (s, 6H), 0.84-0.76 (m, 2H), 0.63-0.56 (m, 2H). B29: (R)-N-cyclopropyl-4-(5-((1- hydroxybutan-2-yl)amino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₆N₆O₃ + H]⁺ 493.3 493.5 12 mg (11%, 2 steps); cream solid free base SMs: (R)-tert-butyl (3-bromo-5-((1-hydroxybutan-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl) ((tetrahydro-2H-pyran-4-yl)methyl)carbamate (115 mg, 0.23 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (209 mg, 0.69 mmol), PdCl₂dppf•DCM (19 mg, 0.023 mmol, 10 mol %); TFA (3 mL) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 6.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 4.11-4.08 (br, s, 1H), 3.98-3.95 (m, 2H), 3.75-3.69 (m, 2H), 3.46-3.40 (m, 2H), 3.23 (d, J = 6.4 Hz, 2H), 2.88-2.82 (m, 1H), 2.45 (s, 3H), 2.01-1.82 (m, 1H), 1.84-1.74 (m, 3H), 1.67-1.60 (m, 1H), 1.43-1.34 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H), 0.84-0.79 (m, 2H), 0.63-0.60 (m, 2H). B30: N-cyclopropyl-4-(5-(((2S,3S)-2- hydroxypentan-3-yl)amino)-7- (((tetrahydro-2H-pyran-4-yl)methyl) amino)pyrazolo[1,5-a]pyrimidin-3- yl)-2-methylbenzamide

[C₂₈H₃₈N₆O₃ + H]⁺ 507.3 507.5 2.25 g, 11% (2 steps); off white solid; free base SMs: tert-butyl (3-bromo-5-(((2S,3S)-2-hydroxypentan-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (9.0 g, 17.5 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (8.46 g, 28 mmol), PdCl₂dppf•DCM (1.35 g, 1.65 mmol, 9.5 mol %), 2M K₃PO₄ (17.6 mL, 35 mmol); TFA (14.6 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.98 (s, 1H), 7.89 (dd, J = 7.6, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.44 (s, 1H), 4.07-3.96 (m, 4H), 3.47-3.41 (m, 2H), 3.24 (d, J = 6.8 Hz, 2H), 2.87-2.82 (m, 1H), 2.45 (s, 3H), 2.06-1.99 (m, 11-0, 1.81-1.67 (m, 3H), 1.65-1.61 (m, 1H), 1.45-1.34 (m, 2H), 1.22 (d, J = = 6.0 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.74-0.79 (m, 210, 0.64-0.60 (m, 2H). HPLC Purity: 97.6% at 254 nM B31: N-cyclopropyl-4-(7-((((1r,4r)-4- hydroxycyclohexyl)methyl)amino)- 5-phenoxypyrazolo[1,5-a]pyrimidin- 3-yl)-2-methylbenzamide

[C₃₀H₃₃N₅O₃ + H]⁺ 512.2; 512.2 49 mg (24%, 2 steps); white solid; free base SMs: (1r,4r)-4-(((3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)- methyl)cyclohexanol (179 mg, 0.33 mmol) and N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (99 mg, 0.35 mmol); DCE (12 mL), TFA (5 mL), 80° C., 1 h. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.18 (s, 1 H), 7.70 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.43-7.35 (m, 2H), 7.25-7.19 (m, 3H), 7.17 (d, J = 8.03 Hz, 1H), 6.57-6.49 (m, 1H), 5.60 (s, 1H), 3.58-3.47 (m, 1H), 3.26-3.14 (m, 2H), 2.83-2.75 (m, 1H), 2.26 (s, 3H), 2.03-1.95 (m, 2H), 1.92-1.84 (m, 2H), 1.76- 1.56 (br, s, 2H), 1.33-1.19 (m, 2H), 1.15-1.00 (m, 2H), 0.83-0.74 (m, 2H), 0.60-0.46 (m, 2H); HPLC purity: 97.1% at 254 nm. B32: N-cyclopropyl-4-(7-((2-hydroxy-2- methylpropyl)amino)-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.5 78 mg (20%, 2 steps); beige solid; TFA salt SMs: tert-butyl (3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(2- ((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate (228 mg, 0.39 mmol), N-cyclopropyl-2-meth- yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (141 mg, 0.47 mmol), PdCl₂dppf•DCM (32 mg, 0.039 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85 (s, 1H), 7.37-7.27 (m, 3H), 703 (br, s, 1H), 6.31 (br, s, 1H), 5.05 (s, 1H), 4.09-3.96 (m, 2H), 3.63 (br, s, 1H), 3.56-3.48 (m, 2H), 3.23-3.13 (m, 2H), 2.99-2.86 (m, 1H), 2.45 (s, 3H), 2.01-1.92 (m, 2H), 1.83-1.68 (m, 2H), 1.38 (s, 6 H), 0.94-0.83 (m, 2H), 0.66-0.59 (m, 2H). B33: N-cyclopropyl-4-(7-((((1r,4r)-4- hydroxycyclohexyl)methyl)amino)- 5-((tetrahydro-2H-pyran-4- yl)amino)pyrazolo[1,5-a]pyrimidin- 3-yl)-2-methylbenzamide

[C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.2 71 mg (42%, 2 steps) white solid TFA salt SMs: SMs: (1r,4r)-4-(((3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(4-methoxybenzyl)amino)methyl)cyclohexanol (0.179 g, 0.328 mmol) and N-cyclopropyl-2- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.282 g, 1.06 mmol); DCE (22 mL), TFA (5 mL), 80° C., 1 h. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.48 (s, 1H), 7.46-7.40 (m, 2H), 5.60 (s, 1H), 4.06- 3.95 (m, 3 H), 3.67-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 3.42 (d, J = 7.03 Hz, 2 H), 2.92-2.85 (m, 1H), 2.47 (s, 3 H), 2.1-1.97 (m, 4 H), 1.86-1.69 (m, 2H), 1.85-1.71 (m, 1 H), 1.71-1.58 (m, 2H), 1.35-1.10 (m, 4 H), 0.89-0.79 (m, 2 H), 0.67-0.60 (m, 2 H).

Example C28: Synthesis of tert-butyl tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

According to general Method F, using tert-butyl 4-(((3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5a] pyrimidin-7-yl)(tert-butoxycarbonyl)amino) methyl)-4-fluoropiperidine-1-carboxylate (7.78 g, 12.2 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (5.14 g, 17.1 mmol), PdCl₂dppfDCM (1.0 g, 1.22 mmol), 2M K₃PO₄ (15 mL, 30 mmol) and THF (60 mL) by heating at reflux in an oil bath for 6 h, crude tert-butyl 4-(((tert-butoxycarbonyl)(3-(4-(cyclopropylcarbamoyl)-3-methylphenyl)-5-(3-fluorophenoxy)pyrazolo [1,5-a]pyrimidin-7-yl)amino)methyl)-4-fluoropiperidine-1-carboxylate was obtained as a yellow solid (8.93 g, 100%). MS ESI 677.3 [M-C₄H₈]⁺, calcd for [C₃₉H₄₆F₂N₆O₆— C₄H₈]⁺ 677.3.

The above compound (8.93 g) was dissolved in DCM (50 mL) and treated with TFA (20 mL) at rt for 19 h. After reaction completion, solvent was removed in vacuo and the crude was redissolved in DCM (2 mL), neutralized with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic extracts were dried over MgSO₄, filtered and concentrated. The crude product was purified by flash chromatography (gradient: 100% EtOAc then MeOH/DCM 0-20%) using three columns in parallel to give N-cyclopropyl-4-(5-(3-fluorophenoxy)-7-(((4-fluoropiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamide as a yellow solid (4.25 g, 65% over 2 steps). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.65-9.45 (m, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.46-7.36 (m, 1H), 7.09 (d, J=7.3 Hz, 2H), 7.04-6.94 (m, 1H), 6.62 (t, J=6.8 Hz, 1H), 5.86 (br, s, 1H), 5.76 (s, 1H), 3.58 (d, J=6.8 Hz, 1H), 3.53 (d, J=6.5 Hz, 1H), 2.99 (dd, J=8.3, 2.8 Hz, 4H), 2.89 (dd, J=7.0, 3.8 Hz, 1H), 2.37 (s, 3H), 2.08-1.94 (m, 2H), 1.80-1.64 (m, 3H), 0.94-0.82 (m, 2H), 0.66-0.55 (m, 2H); MS ESI 533.3 [M+H]⁺, calcd for [C₂₉H₃₀F₂N₆O₂+H]⁺ 533.2.

A solution of formaldehyde solution (1 mL, 11.97 mmol, 37 wt. % in H₂O), N-cyclopropyl-4-(5-(3-fluorophenoxy)-7-(((4-fluoropiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenz-amide (4.25 g, 7.98 mmol), and AcOH (1 mL) was stirred at rt for 30 min. NaBH(OAc)₃ (3.38 g, 15.96 mmol) was then added and the resulting mixture was stirred at rt for 1 h. Sat. NaHCO₃ and DCM were added to separate the phases and the aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO₄, filtered and concentrated. The crude product was purified by RP flash chromatography (gradient: EtOAc/hex 5-100%) using three columns in parallel, followed by Water PoraPak Rxn cartridge (three cartridges in parallel) to give the free base as a white solid (2.13 g, 49%). The free base was dissolved in a mixture of DCM (20 mL) and MeOH (40 mL), HCl (4.7 mL, 4.7 mmol, 1M Et₂O) was then added slowly. Solvent was removed in vacuo to give a HCl salt as a pale yellow solid (2.25 g, 49%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.39 (s, 1H), 7.84 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54-7.40 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.16-6.98 (m, 3H), 6.05 (s, 1H), 3.80 (d, J=18.1 Hz, 2H), 3.54 (d, J=12.3 Hz, 2H), 3.29-3.23 (m, 2H), 2.94 (s, 3H), 2.88-2.79 (m, 1H), 2.42-2.29 (m, 2H), 2.28 (s, 3H), 2.19 (br, s, 2H), 0.87-0.73 (m, 2H), 0.68-0.55 (m, 2H); MS ESI 547.2 [M+H]⁺, calcd for [C₃₀H₃₂F₂N₆O₂+H]⁺ 547.3; HPLC purity: 100% at 254 nm.

Example C29: (S)—N-cyclopropyl-2-methyl-4-(7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-5-(((tetrahydrofuran-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

According to General Method J, to a mixture of (S)-(tetrahydrofuran-2-yl)methanamine (51 mg, 0.5 mmol) and iPr₂NEt (0.175 mL, 1 mmol) was added 0.2 M solution of tert-butyl (3-(4-(cyclopropylcarbamoyl)-3-methylphenyl)-5-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate in NMP (2 mL, 0.4 mmol). The resulting mixture was heated in microwave at 120° C. for 2 h.

2 mL of H₂O was added to the above reaction and the mixture was heated in microwave at 140° C. for 2 h. After passing through porapak, it was purified by RP Biotage C18 column (gradient: CH₃CN/H₂O (0.1% TFA) 0-60%) and porapak to give the title compound as a white solid.

It was redissolved in MeOH (10 mL) and 0.4 mL of 1 M HCl in Et₂O (0.4 mmol) was added. After removal of solvents, it was redissolved in MeOH and repeated twice to give the HCl salt of the title compound as light yellow solid (98.7 mg, 46%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.55-7.35 (m, 3H), 4.30-4.12 (m, 1H), 4.05-3.35 (m, 10H), 2.92-2.85 (m, 1H), 2.47 (s, 3H), 2.20-1.92 (m, 4H), 1.86-1.68 (m, 3H), 1.55-1.38 (m, 2H), 0.85-0.78 (m, 2H), 0.70-0.60 (m, 2H); MS ESI 505.3 [M+H]⁺, [C₂₈H₃₆N₆O₃+H]⁺ 505.3; HPLC purity: 98.5% at 254 nm

Example C30: 3-((3-(4-(cyclopropylcarbamoyl)-3-methylphenyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)pyridine 1-oxide

The N-cyclopropyl-2-methyl-4-(5-(pyridin-3-yloxy)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino) pyrazolo[1,5-a]pyrimidin-3-yl)benzamide hydrochloride (100 mg, 0.186 mmol) was dissolved in MeOH and turned into free base by running through PoraPak. The resulting free base was dissolved in DCM (4 mL) and was added mCPBA (75%, 126 mg, 0.56 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at rt for 3.5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (MeOH/DCM 0-10%) to give the intermediate as brown solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.33 (s, 1H), 8.29 (dt, J=4.8, 2.1 Hz, 1H), 7.70 (s, 1H), 7.63-7.56 (m, 3H), 7.22 (d, J=8.0 Hz, 1H), 5.87 (s, 1H), 3.97 (dd, J=11.4, 3.1 Hz, 2H), 3.42 (td, J=11.7, 1.9 Hz, 2H), 3.31 (d, J=4.8 Hz, 2H), 2.85 (td, J=7.3, 3.6 Hz, 1H), 2.32 (s, 3H), 2.01 (d, J=11.8 Hz, 1H), 1.74 (d, J=11.0 Hz, 2H), 1.45-1.32 (m, 2H), 0.85-0.77 (m, 2H), 0.65-0.57 (m, 2H). HPLC purity: 99.1% at 254 nm.

The following final compounds were synthesized according to the synthesis of Example B1 or C28 using General Method F:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]+ Salt form C31: N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-((2- morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₁FN₆O₃ + H]⁺ 531.3; 531.3 3.332 g, 59% (2 steps); white solid; HCl salt SMs: tert-butyl (5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (5.42 g, 10 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (6.33 g, 21 mmol), PdCl₂dppf•DCM (408 mg, 0.5 mmol, 5 mol %), 2M K₃PO₄ (15 mL, 30 mmol); TFA (10 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.42 (s, 1H), 7.84 (s, 1H), 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 7.53- 7.47 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16-7.06 (m, 3H), 6.08 (s, 1H), 4.17-4.08 (m, 2H), 3.97 (t, J = 6.2 Hz, 2H), 3.94 (t, J = 11.8 Hz, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.57 (t, J = 6.2 Hz, 2H), 3.35-3.27 (m, 2H), 2.38-2.31 (m, 3H), 2.27 (s, 3H), 0.84-0.78 (m, 2H), 0.63-0.58 (m, 2H). HPLC purity: 98.9% at 254 nm C32: N-cyclopropyl-4-(5-(2,3- difluorophenoxy)-7-((2- morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₀F₂N₆O₃ + H]⁺ 549.2; 549.2 2.84 g, 45% (2 steps); white solid; TFA salt SMs: tert-butyl (3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2- morpholinoethyl)carbamate (5.31 g, 9.54 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide (4.32 g, 14.31 mmol), PdCl₂dppf•DCM (390 mg, 0.477 mmol, 5 mol %), 2M K₃PO₄ (11.46 mL, 22.92 mmol); TFA (10 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (s, 1H), 7.75 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 6.3 Hz, 2H), 7.19 (d, J = 7.3 Hz, 2H), 6.14 (s, 1H), 4.18-3.76 (m, 6H), 3.59 (t, J = 5.5 Hz, 4H), 3.42- 3.25 (m, 2H), 2.89-2.78 (m, 1H), 2.24 (s, 3H), 0.85-0.76 (m, 2H), 0.66-0.55 (m, 2H). HPLC purity: 98.3% at 254 nm C33: 2-chloro-N-cyclopropyl-4-(5-(2,3- difluorophenoxy)-7-((2- morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₇ClF₂N₆O₃ + H]⁺ 569.2; 569.3 3.08 g, 51% (2 steps); white solid; HCl salt SMs: tert-butyl (3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2- morpholinoethyl)carbamate (5.82 g, 10 mmol), (3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (5.88 g, 24.5 mmol), PdCl₂dppf•DCM (272 mg, 0.333 mmol), 2M K₃PO₄ (5 mL, 10 mmol); TFA (10 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (s, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.70 (dd, J = 8.0, 1.8 Hz, 1H), 7.29-7.24 (m, 3H), 7.21-7.15 (m, 1H), 6.01 (s, 1H), 3.76-3.74 (m, 4H), 3.62 (t, J = 6.3 Hz, 2H), 2.85 (tt, J = 7.3, 3.5 Hz, 1H), 2.78 (t, J = 6.3 Hz, 2H), 2.64-2.56 (m, 4H), 0.84-0.77 (m, 2H), 0.66- 0.60 (m, 2H). HPLC purity: 98.2% at 254 nm C34: 2-chloro-N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-((2- morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₈ClFN₆O₃ + H]⁺ 551.2; 551.2 218 mg, 33% (2 steps); white solid; TFA salt SMs: tert-butyl (5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (540 mg, 1 mmol), (3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (335 mg, 1.4 mmol), PdCl₂dppf•DCM (41 mg, 0.05 mmol, 5 mol %), 2M K₃PO₄ (1.5 mL, 3 mmol); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.26 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.2, 1.4 Hz, 1H), 7.47-7.41 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.09-7.00 (m, 3H), 5.90 (s, 1H), 4.10-3.80 (m, 6H), 3.70-3.51 (m, 4H), 3.35-3.20 (m, 2H), 2.89-2.83 (m, 3H), 0.84-0.78 (m, 2H), 0.67-0.62 (m, 2H). HPLC purity: 97.7% at 254 nm C35: N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7-((((R)- tetrahydrofuran-3- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 4.2 g, 46% (2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(((R)-tetrahydrofuran-3-yl)methyl)carbamate (9.14 g, 17.96 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (8.11 g, 26.94 mmol), PdCl₂dppf•DCM (1466 mg, 1.796 mmol, 10 mol %), 2M K₃PO₄ (31 mL, 62.85 mmol), THF (100 mL); TFA (18 mL), DCM (18 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 8.0, 1.3 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.45 (d, J = 0.8 Hz, 1H), 4.23-4.11 (m, 2H), 3.93 (td, J = 8.2, 5.5 Hz, 1H), 3.85 (m, J = 7.3 Hz, 1H), 3.77 (q, J = 7.9 Hz, 1H), 3.65 (dd, J = 8.4, 5.1 Hz, 1H), 3.31-3.28 (m, 2H), 2.90- 2.81 (m, 1H), 2.75-2.65 (m, 1H), 2.46 (s, 3H), 2.20-2.07 (m, 1H), 1.94-1.61 (m, 7H), 1.48 (d, J = 9.0 Hz, 2H), 0.85-0.78 (m, 2H), 0.66-0.60 (m, 2H). HPLC purity: 99.1% at 254 nm C36: N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7-((((S)- tetrahydrofuran-3- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₈H₃₆N₆O₃ + H]⁺ 505.2; 505.4 3.10 g, 16% (2 steps); pale yellow solid; free base SMs: tert-butyl (3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(((S)-tetrahydrofuran-3-yl)methyl)carbamate (10.5 g, 20.5 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9.29 g, 30.8 mmol), PdCl₂dppf•DCM (1.69 g, 2.05 mmol, 10 mol %), 2M K₃PO₄ (20.6 mL, 41.1 mmol); TFA (13 mL). ¹H NMR identical to C8. 402237. HPLC purity: 98.3% at 254 nM. C37: N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7- ((oxetan-3- ylmethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2 75 mg, 69% (2 steps); white solid; free base SMs: tert-butyl (3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(oxetan-3-ylmethyl)carbamate (338 mg, 0.681 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (226 mg, 0.749 mmol), PdCl₂dppf•DCM (56 mg, 0.068 mmol, 10 mol %), 2M K₃PO₄ (1 mL, 2.04 mmol); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H), 4.88-4.83 (m, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.11-4.22 (m, 2H), 3.64 (d, J = 7.3 Hz, 2H), 3.46-3.37 (m, 1H) 2.90-2.81 (m, 1H), 2.46 (s, 3H), 1.92-1.62 (m, 6H), 1.54-1.43 (m, 2H), 0.86-0.78 (m, 2H), 0.66-0.60 (m, 2H). HPLC purity: 99.2% at 254 nm C38: (S)-N-cyclopropyl-4-(5-((1-hydroxy- 3-methylbutan-2-yl)amino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₈H₃₈N₆O₃ + H]⁺ 507.3; 507.5 1.98 g, 48% (2 steps); cream solid; free base SMs: (S)-tert-butyl (3-bromo-5-((1-hydroxy-3-methylbutan-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (6.0 g, 11.7 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (5.28 g, 17.5 mmol), PdCl₂dppf•DCM (0.956 g, 1.75 mmol, 10 mol %), 2M K₃PO₄ (11.72 mL, 23.4 mmol); TFA (10.5 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 5.69 (s, 1H), 3.98 (dd, J = 11.2, 3.2 Hz, 2H), 3.84 (br, s, 1H), 3.76-3.68 (m, 2H), 3.46-3.41 (m, 4H), 2.91-2.85 (m, 1H), 2.47 (s, 3H), 2.09-2.03 (m, 2H), 1.76-1.73 (m, 2H), 1.47-1.37 (m, 2 H), 1.08 (t, J = 7.2 Hz, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H). HPLC Purity (HCl salt): 99.0% at 254 nM. C39: N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 1.98 g, 20% (2 steps); cream solid; free base SMs: tert-butyl (3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.95 g, 15 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.84 g, 23 mmol), PdCl₂dppf•DCM (1.21 g, 1.50 mmol, 10 mol %), 2M K₃PO₄ (15.14 mL, 30 mmol); TFA (17 mL). ¹H NMR (400 MHz, CD₃Cl₃) δ ppm 8.10 (s, 1H), 7.91 (s, 1H), 7.78-7.76 (m, 1H), 7.35 (s, 1H), 7.34 (s, 1H),6.09 (t, J = 6.0Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.12 (s, 1H), 4.98 (d, J = 6.8 Hz, 1H), 4.20- 4.15 (m, 2H), 4.00 (dd, J = 11.6, 3.6 Hz, 2H), 3.42-3.36 (m, 2H), 3.15 (t, J = 6.8 Hz, 2H), 2.93-2.87 (m, 1H), 2.51 (s, 3H), 1.97-1.88 (m, 3H), 1.85-1.51 (m, 6H), 1.50-1.41 (m, 2H), 1.39-1.33 (m, 2H), 0.90-0.85 (m, 2H), 0.63-0.59 (m, 2H). HPLC Purity (HCl salt): 98.3% at 254 nM. C40: (S)-N-cyclopropyl-4-(5-((2- hydroxy-2,4-dimethylpentan-3- yl)amino)-7-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₄₂N₆O₃ + H]⁺ 535.3; 535.3 1.45 g, 12% (2 steps); cream solid; free base SMs: (S)-tert-butyl (3-bromo-5-((2-hydroxy-2,4-dimethylpentan-3-yl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (5.50 g, 10.1 mmol), N-cyclopropyl- 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.59 g, 15.2 mmol), PdCl₂dppf•DCM (0.825 g, 1.01 mmol, 10 mol %), 2M K₃PO₄ (10.18 mL, 20.2 mmol); TFA (8.4 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.53 (s, 1H), 4.33 (s, 1H), 3.92 (dd, J = 11.2, 3.2 Hz, 2H), 3.45-3.35 (m, 2H), 3.32-3.31 (m, 1H), 3.18-3.16 (m, 2H), 2.87-2.82 (m, 1H), 2.45 (s, 3H), 2.31-2.24 (m, 1H), 1.95-1.85 (m, 1H), 1.85-1.67 (m, 2H), 1.37-1.30 (m, 4H), 1.27 (s, 3H), 1.07-1.03 (m, 6H), 0.82-0.78 (m, 2H), 0.64-0.60 01, 2H). HPLC Purity (HCl salt): 99.1% at 254 nM. C41: (S)-N-cyclopropyl-4-(5-((1- cyclopropyl-2-hydroxy-2- methylpropyl)amino)-7- (((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₄₀N₆O₃ + H]⁺ 533.3; 533.4 2.10 g, 17% (2 steps); pale yellow solid; free base SMs: (S)-tert-butyl (3-bromo-5-((1-cyclopropyl-2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.50 g, 13.9 mmol), N-cyclopropyl- 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.27 g, 20.8 mmol), PdCl₂dppf•DCM (1.13 g, 1.39 mmol, 10 mol %), 2M K₃PO₄ sol (13.9 mL, 27.8 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 7.96 (s, 1H), 7.77 (dd, J = 8.4, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H), 3.96 (dd, J = 11.2, 3.2 Hz, 2H), 3.61-3.58 (m, 1H), 3.41 (t, J = 11.6 Hz, 2 H), 3.22-3.20 (m, 2H), 2.88-2.82 (m, 1H), 2.45 (s, 3H), 2.02-1.96 (m, 1H), 1.75-1.72 (m, 2H), 1.42-1.32 (m, 8H), 1.16-1.09 (m, 1H), 0.83-0.78 (m, 2H), 0.73-0.68 (m, 1H), 0.64-0.60 (m, 2H), 0.50-0.39 (m, 3H). HPLC Purity: 98.2% at 254 nM. C42: N-cyclopropyl-4-(7- ((cyclopropylmethyl)amino)-5- (((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.3 2.09 g, 25% (2 steps); pale yellow solid; HCl salt SMs: tert-butyl (3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(cyclopropylmethyl)carbamate (8.48 g, 17.7 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.92 g, 23.0 mmol), PdCl₂dppf•DCM (1.44 g, 1.76 mmol), 2M K₃PO₄ (26.6 mL, 106.2 mmol); TFA (20 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.51-7.37 (m, 3H), 5.67 (br, s, 1H), 4.04-3.82 (m, 2H), 3.46-3.37 (m, 2H), 2.93-2.82 (m, 1H), 2.47 (s, 3H), 1.89-1.64 (m, 6H), 1.61-1.42 (m, 2H), 1.31- 1.21 (m, 1H), 0.88-0.78 (m, 2H), 0.70-0.58 (m, 4H), 0.46-0.36 (m, 2H). HPLC purity: 98% at 254 nm. C43: N-cyclopropyl-4-(7-((((1s,3s)-3- hydroxy-3- methylcyclobutyl)methyl)amino)-5- (pyridin-3-yloxy)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₈H₃₀N₆O₃ + H]⁺ 499.2; 499.3 96 mg, 47% (2 steps); beige solid; HCl salt SMs: tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.23 g, 0.38 mmol), N-cyclopropyl-2- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.15 g, 0.49 mmol), PdCl₂dppf•DCM (0.031 g, 0.038 mmol), 2M K₃PO₄ (0.57 mL, 1.14 mmol); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 9.14 (br, s, 1H), 8.89-8.82 (m, 1H), 8.79-8.71(m, 1H), 8.40 (s, 1H), 8.31-8.21 (m, 1H), 7.68 (s, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 3.56 (d, J = 6.5 Hz, 2H), 2.88-2.79 (m, 1H), 2.40-2.31 (m, 1H), 2.29 (s, 3H), 2.26-2.18 (m, 2H), 1.99- 1.89 (m, 2H), 1.37 (s, 3H), 0.85-0.76 (m, 2H), 0.63-0.53 (m, 2H). HPLC purity: 99.5% at 254 nm. C44: 4-(5-(cyclopentylamino)-7- ((((1s,3s)-3-hydroxy-3- methylcyclobutyl)methyl)amino) pyrazolo[1,5-a]pyrimidin-3-yl)-N- cyclopropyl-2-methylbenzamide

[C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.4 75 mg, 21% (2 steps); light orange solid; HCl salt SMs: tert-butyl (3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.40 g, 0.67 mmol), N-cyclopropyl-2- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.26 g, 0.88 mmol), PdCl₂dppf•DCM (0.055 g, 0.067 mmol), 2M K₃PO₄ (1 mL, 2.01 mmol); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.42 (s, 3H), 5.52 (br, s, 1H), 4.23-4.11 (m, 1H), 3.68-3.54 (m, 2H), 2.93-2.81 (m, 1H), 2.46 (s, 3H), 2.38-2.27 (m, 1H), 2.26-2.07 (m, 4H), 1.99-1.89 (m, 2H), 1.88-1.59 (m, 6H), 1.35 (s, 3H), 0.86-0.79 (m, 2H), 0.66-0.58 (m, 2H). HPLC purity: 99% at 254 nm. C45: N-cyclopropyl-4-(5-((1- (hydroxymethyl)cyclopentyl)amino)- 7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.5 83 mg, 16 mg (2 steps); white solid; TFA salt SMs: tert-butyl(3-bromo-5-((1(hydroxymethyl)cyclopentyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl) methyl)carbamate (437 mg, 0.83 mmol), N-cyclopropyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (350 mg, 1.2 mmol), PdCl₂dppf•DCM (68 mg, 0.0.083 mmol), and 2 M K₃PO₄ (1.3 mL, 2.5 mmol); TFA (6 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.51 (br, s, 1H), 7.94 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.26-7.20 (m, 2H), 6.78 (br, s, 1H), 5.73 (br, s, 1H), 3.97 (dd, J = 11.2, 3.4 Hz, 2H), 3.66 (s, 2H), 3.37 (t, J = 11.2 Hz, 2H), 3.19 (t, J = 5.9 Hz, 2H), 2.92-2.79 (m, 1H), 2.44 (s, 3H), 2.04-1.53 (m, 11H), 1.43-1.23 (m, 2H), 0.91-0.75 (m, 2H), 0.70-0.56 (m, 2H). HPLC purity: 99.5% at 254 nm C46: N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-(((1- methylpiperidin-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₃₃FN₆O₂ + H]⁺ 529.3 529.3 116 mg, 29% (2 steps); off white powder; TFA salt SMs: tert-butyl (3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)((1-methylpiperidin-4- yl)methyl)carbamate (0.338, 0.63 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (0.381 g, 1.3 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.39 (s, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.53-7.45 (m, 1H), 7.21 (d, J = 7.80 Hz, 1H), 7.14-7.04 (m, 3H), 5.95 (s, 1H), 3.61-3.54 (m, 2H), 3.46 (d, J = 6.0 Hz, 2H), 3.09-2.98 (m, 2H), 2.89 (s, 3H), 2.86-2.79 (m, 1H), 2.28 (s, 3H), 2.10-2.22 (m, 3H), 1.66-1.48 (m, 2H), 0.84-0.72 (m, 2H), 0.67-0.55 (m, 2H). HPLC Purity (HCl salt): 97.7% at 254 nM C47: N-cyclopropyl-4-(5-(2,3- difluorophenoxy)-7-((2-(4- fluoropiperidin-1- yl)ethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₃₁F₃N₆O₂ + H]⁺ 565.2 565.4 86 mg, 23% (2 steps); white powder; TFA salt SMs: tert-butyl (3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-(4- fluoropiperidin-1-yl)ethyl)carbamate (315 mg, 0.55 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.244 g, 0.81 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.20 (s, 1H), 7.66 (s, 1H), 7.46 (d, J = 6.5 Hz, 1H), 7.33 (br. s., 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.19-7.08 (m, 3H), 5.99 (d, J = 2.5 Hz, 1H), 5.10-4.93 (m, 1H), 3.94 (q, J = 5.8 Hz, 2H), 3.64 (br. s., 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.15 (br. s., 2H), 2.95-2.85 (m, 1H), 2.45-2.15 (m, 4H), 2.30 (s, 3H), 0.99-0.82 (m, 2H), 0.67-0.57 (m, 2H). HPLC Purity: 99.7% at 254 nM

The following final compounds were synthesized according to the synthesis of Example B1, C28 or C29 using General Method F or J:

Example number MS calcd; MS ESI [M + H]⁺ Salt Form; Structure HPLC purity ¹H NMR

C48 [C₂₉H₃₈N6O₃ + H]⁺ 519.3; 519.5 TFA salt; 93.9% at 254 nm (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.52-7.36 (m, 3H), 5.58 (s, 1H), 3.99 (dd, J = 11.2, 3.4 Hz, 2H), 3.81-3.71 (m, 1H), 3.70-3.60 (m, 1H), 3.52- 3.39 (m, 4H), 2.87 (dq, J = 7.3, 3.7 Hz, 1H), 2.46 (s, 3H), 2.18-1.95 (m, 5H), 1.75 (d, J = 12.3 Hz, 2H), 1.59-1.36 (m, 6H), 0.87-0.77 (m, 2H), 0.67- 0.59 (m, 2H).

C49 [C₂₈H₃₁N₇O₂ + H]⁺ 498.3; 498.4; di-TFA salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.92 (br, s, 1H), 8.80 (d, J = 5.5 Hz, 1H), 8.63-8.52 (m, 1H), 8.23 (s, 1H), 8.07-7.96 (m, 1H), 7.73-7.45 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 5.55 (s, 1H), 3.96 (d, J = 11.8 Hz, 3H), 3.61-3.49 (m, 2H), 3.36-3.29 (s, 2H), 2.88 (tt, J = 7.3, 3.8 Hz, 1H), 2.46 (s, 3H), 1.98 (d, J = 12.0 Hz, 2H), 1.67-1.50 (m, 2H), 0.88-0.78 (m, 2H), 0.68-0.60 (m, 2H).

C50 [C₂₈H₃₀N₆O₃ + H]⁺ 499.3; 499.5; TFA salt; 98.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.97 (d, J = 7.8 Hz, 1H), 8.57-8.55 (m, 1H), 8.01-7.97 (m, 1H), 7.94 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.59 (s, 1H), 3.99 (dd, J = 11.0, 3.3 Hz, 2H), 3.51-3.41 (m, 5H), 2.88 (tt, J = 7.3, 3.8 Hz, 1H), 2.47 (s, 3H), 2.16-2.07 (m, 1H), 1.83-1.76 (m, 2H), 1.51-1.39 (m, 2H), 0.87-0.80 (m, 2H), 0.66-0.62 (m, 2H).

C51 [C₂₈H₃₁N₇O₃ + H]⁺ 514.3; 514.2 di-TFA salt: 98% at 254 nm (400 MHz, CD₃OD) δ ppm 8.73 (br, s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.84-7.77 (m, 1H), 7.72 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 4.19-3.77 (m, 6H), 3.73-3.51 (m, 4H), 3.25-3.41 (m, 2H), 2.88-2.80 (m, 1H), 2.28 (s, 3H), 0.88-0.74 (m, 2H), 0.66-0.56 (m, 2H).

C52 [C₂₈H₃₀N₆O₃ + H]⁺ 499.3; 499.2 TFA salt; 96.7% at 254 nm (400 MHz, CD₃OD) δ ppm 8.91 (s, 1H), 8.79 (d, J = 5.8 Hz, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.39 (s, 1H), 8.06 (dd, J = 8.0, 5.8 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 5.58 (s, 1H), 5.34 (tt, J = 8.5, 4.3 Hz, 1H), 4.89 (s, 2H), 3.97 (dt, J = 11.6, 4.5 Hz, 2H), 3.63 (ddd, J = 11.6, 9.2, 2.5 Hz, 2H), 2.87 (tt, J = 7.3, 3.7 Hz, 1H), 2.45 (s, 3H), 2.20-2.12 (m, 2H), 1.84-1.72 (m, 2H), 0.86-0.79 (m, 2H), 0.66-0.61 (m, 2H).

C53 [C₂₈H₃₇N₇O₃ + H]⁺ 520.3; 502.3 di-TFA salt; 98.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.79-7.65 (m, 1H), 7.64-7.53 (m, 1H), 7.38 (d, J = 7.3 Hz, 1H), 5.65 (br, s, 1H), 4.18-3.82 (m, 8H), 3.70-3.50 (m, 5H), 3.22-3.42 (m, 4H), 2.92-2.82 (m, 1H), 2.46 (s, 3H), 2.16-2.03 (m, 2H), 1.72-1.58 (m, 2H), 0.89-0.78 (m, 2H), 0.68-0.60 (m, 2H).

C54 [C₂₉H₃₀F₂N₆O₃ + H]⁺ 549.2; 549.2 TFA salt; 99.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.84 (d, J = 5.5 Hz, 2H), 8.27 (s, 1H), 8.08 (d, J = 6.8 Hz, 2H), 7.77- 7.65 (m, 1H), 7.64-7.54 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.54-5.41 (m, 1H), 5.08 (br, s, 2H), 4.01-3.90 (m, 3H), 3.53 (td, J = 11.4, 2.0 Hz, 2H), 2.88 (tt, J = 7.3, 3.8 Hz, 1H), 2.47 (s, 3H), 2.02-1.93 (m, 2H), 1.64-1.51 (m, 2H), 0.88- 0.80 (m, 2H), 0.67-0.61 (m, 2H).

C55 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.2 TFA salt; 99.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.38-7.54 (m, 3H), 5.50 (s, 1H), 4.12-4.03 (m, 1H), 3.99 (dd, J = 10.9, 4.1 Hz, 2H), 3.49-3.39 (m, 4H), 2.88 (tt, J = 7.4, 3.8 Hz, 1H), 2.47 (s, 3H), 2.13-2.00 (m, 1H), 1.79-1.71 (m, 2H), 1.50-1.38 (m, 2H), 1.35 (d, J = 6.5 Hz, 6H), 0.88-0.79 (m, 2H), 0.67-0.61 (m, 2H).

C56 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.2 free base; 97.9% at 254 nm ¹H NMR (400 MHz, CDCl₃) δ ppm 8.50 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.26 (s, 1H), 7.72 (s, 1H), 7.61-7.55 (m, 2H), 7.30-7.28 (m, 1H), 6.54-6.49 (m, 1H), 5.85 (br, s, 1H), 5.75 (s, 1H), 4.06 (dd, J = 10.9, 4.1 Hz, 2H), 3.45 (td, J = 12.0, 2.1 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 2.93-2.87 (m, 1H), 2.40 (s, 3H), 2.12-1.99 (m, 1H), 1.80 (d, J = 11.0 Hz, 2H), 1.50 (td, J = 12.1, 3.9 Hz, 2H), 0.92- 0.84 (m, 2H), 0.65-0.58 (m, 2H).

C57 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 TFA salt; 96.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.55-7.37 (m, 3H), 4.05-3.94 (m, 4H), 3.51-3.35 (m, 8H), 2.88 (tt, J = 7.3, 3.7 Hz, 1H), 2.47 (s, 3H), 2.13- 1.91 (m, 2H), 1.81-1.72 (m, 4H), 1.43 (qd, J = 12.3, 4.6 Hz, 4H), 0.88-0.80 (m, 2H), 0.67-0.61 (m, 2H).

C58 [C₂₉H₃₈N₆O₂ + H]⁺ 503.3; 503.3 free base; 98.2% at 254 nm (400 MHz, CDCl₃) δ ppm 8.15 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.11 (t, J = 5.8 Hz, 1H), 5.94 (br, s, 1H), 5.29 (s, 1H), 5.05 (t, J = 8.4 Hz, 1H), 4.04 (dd, J = 11.4, 3.6 Hz, 2H), 3.43 (td, J = 11.8, 2.0 Hz, 2H), 3.25 (t, J = 6.3 Hz, 2H), 3.03 (s, 3H), 2.92 (tq, J = 6.9, 3.7 Hz, 1H), 2.53 (s, 3H), 2.17-2.05 (m, 2H), 2.05-1.94 (m, 2H), 1.84-1.75 (m, 4H), 1.74- 1.59 (m, 3H), 1.53-1.39 (m, 2H), 0.92-0.84 (m, 2H), 0.66-0.59 (m, 2H).

C59 [C₂₈H₃₁N₇O₂ + H]⁺ 498.3; 498.4 TFA salt; 98% at 254 nm (400 MHz, CD₃OD) δ ppm 9.69 (br, s, 1H), 8.64 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 7.96 (dd, J = 8.9, 5.9 Hz, 1H), 7.82-7.86 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 5.68 (s, 1H), 4.00 (dd, J = 11.3, 3.8 Hz, 2H), 3.45 (t, J = 10.8 Hz, 2H), 3.37-3.27 (m, 2H), 2.89 (tt, J = 7.3, 3.9 Hz, 1H), 2.48 (s, 3H), 2.10-2.04 (m, 1H), 1.80-1.78 (m, 2H), 1.48-1.38 (m, 2H), 0.69-0.84 (m, 2H), 0.62- 0.69 (m, 2H).

C60 [C₂₉H₃₃N₇O₂ + H]⁺ 512.3; 512.2 TFA salt; 99.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.32 (s, 1H), 8.15 (s, 1H), 7.84-7.80 (m, 3H), 7.40-7.34 (m, 3H), 7.09- 7.05 (m, 1H), 5.68 (s, 1H), 4.15-3.95 (m, 2H), 3.85 (br, s, 4H), 3.56 (br, s, 4H), 3.37-3.26 (m, 2H), 2.90-2.86 (m, 1H), 2.49 (s, 3H), 0.86-0.81 (m, 2H), 0.69-0.61 (m, 2H).

C61 [C₂₉H₂₉N₇O₂ + H]⁺ 508.2; 508.2 free base; 97.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.32 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J = 7.9, 1.4 Hz, 1H), 7.49-7.41 (m, 2H), 7.32-7.23 (m, 3H), 7.21-7.15 (m, 2H), 7.03 (s, 1H), 5.68 (s, 1H), 4.17 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 6.9 Hz, 2H), 2.83 (tt, J = 7.3, 3.7 Hz, 1H), 2.24 (s, 3H), 2.20 (t, J = 7.0 Hz, 2H), 0.83-0.76 (m, 2H), 0.63-0.57 (m, 2H).

C62 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.3 free base; 97.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 8.09 (s, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 4.32 (quint, J = 6.3 Hz, 1H), 4.16 (qd, J = 6.8, 4.4 Hz, 1H), 3.95-3.86 (m, 1H), 3.81-3.73 (m, 1H), 3.43-3.36 (m, 1H), 3.31- 3.25 (m, 1H), 2.85 (tt, J = 7.3, 3.7 Hz, 1H), 2.44 (s, 3H), 2.19-1.86 (m, 5H), 1.84-1.52 (m, 7H), 0.84-0.77 (m, 2H), 0.66-0.60 (m, 2H).

C63 [C₂₇H₃₄N₆O₂ + H]⁺ 491.3; 491.3 free base; 99.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 4.24-4.12 (m, 2H), 4.06-3.98 (m, 2H), 3.97-3.88 (m, 1H), 3.83-3.75 (m, 1H), 3.60 (td, J = 11.5, 2.0 Hz, 2H), 3.47-3.39 (m, 1H), 3.37- 3.32 (m, 1H), 2.86 (tt, J = 7.3, 3.9 Hz, 1H), 2.45 (s, 3H), 2.19-1.87 (m, 5H), 1.75 (s, 1H), 1.60 (dd, J = 12.7, 4.4 Hz, 2H), 0.86-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C64 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.3 free base; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 8.09 (s, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 4.32 (quint, J = 6.3 Hz, 1H), 4.16 (qd, J = 6.8, 4.4 Hz, 1H), 3.95-3.86 (m, 1H), 3.81-3.73 (m, 1H), 3.43-3.36 (m, 1H), 3.31- 3.25 (m, 1H), 2.85 (tt, J = 7.3, 3.7 Hz, 1H), 2.44 (s, 3H), 2.19-1.86 (m, 5H), 1.84-1.52 (m, 7H), 0.84-0.77 (m, 2H), 0.66-0.60 (m, 2H).

C65 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.3 free base; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 4.24-4.12 (m, 2H), 4.06-3.98 (m, 2H), 3.97-3.88 (m, 1H), 3.83-3.75 (m, 1H), 3.60 (td, J = 11.5, 2.0 Hz, 2H), 3.47-3.39 (m, 1H), 3.37- 3.32 (m, 1H), 2.86 (tt, J= 7.3, 3.9 Hz, 1H), 2.45 (s, 3H), 2.19-1.87 (m, 5H), 1.75 (s, 1H), 1.60 (dd, J = 12.7, 4.4 Hz, 2H), 0.86-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C66 [C₃₀H₃₈N₆O₃ + H]⁺ 531.3; 531.6 free base; 98.5% at 254 nm (400 MHz, CDCl₃) δ ppm 8.15 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 6.08 (t, J = 6.0 Hz, 1H), 5.92 (br, s, 1H), 4.60 (br, s, 2H), 4.13 (s, 1H), 4.04 (dd, J = 11.0, 3.3 Hz, 2H), 3.43 (td, J = 11.9, 1.9 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 2.91 (td, J = 7.1, 3.4 Hz, 1H), 2.53 (s, 3H), 2.41-2.30 (m, 4H), 2.16-2.09 (m, 2H), 2.03- 1.92 (m, 1H), 1.79 (d, J = 14.6 Hz, 4H), 1.52-1.38 (m, 2H), 0.92-0.85 (m, 2H), 0.65-0.59 (m, 2H).

C67 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3 free base; 98.5% at 254 nm (400 MHz, CDCl₃ & drops of CD₃OD) δ ppm 8.12 (s, 1H), 7.89-7.84 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 5.37 (s, 1H), 4.22-4.13 (m, 2H), 4.01 (dd, J = 11.2, 3.9 Hz, 2H), 3.97-3.90 (m, 1H), 3.46-3.37 (m, 2H), 3.30 (ddd, J = 13.2, 9.9, 3.0 Hz, 2H), 3.21 (d, J = 6.8 Hz, 2H), 2.82-2.90 (m, 1H), 2.48 (s, 3H), 2.03-1.93 (m, 3H), 1.81-1.73 (m, 2H), 1.66-1.54 (m, 2H), 1.49-1.36 (m, 2H), 0.90-0.81 (m, 2H), 0.59 (d, J = 2.5 Hz, 2H).

C68 [C₂₆H₃₂N₆O₃ + H]⁺ 477.3; 477.2 free base; 99.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.05 (s, 1H), 7.91 (dd, J = 8.2, 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.44 (quint, J = 7.0 Hz, 1H), 3.98 (dd, J = 11.4, 3.6 Hz, 2H), 3.56 (d, J = 7.8 Hz, 2H), 3.40-3.45 (m, 2H), 3.23 (d, J = 7.0 Hz, 2H), 2.86 (tt, J = 7.4, 3.8 Hz, 1H), 2.62-2.52 (m, 1H), 2.45 (s, 3H), 2.27-2.19 (m, 2H), 2.13-1.96 (m, 3H), 1.80-1.73 (m, 2H), 1.46-1.34 (m, 2H), 0.85-0.79 (m, 2H), 0.66- 0.61 (m, 2H).

C69 [C₂₆H₃₂N₆O₃ + H]⁺ 477.3; 477.2 free base; 99.8% at 254 nm (400 MHz, CDCl₃) δ ppm 8.13 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.12 (t, J = 5.9 Hz, 1H), 5.98 (br. s., 1H), 4.95 (s, 1H), 4.83-4.75 (m, 1H), 4.38 (dd, J = 9.2, 6.9 Hz, 2H), 4.03 (dd, J = 11.7, 3.9 Hz, 2H), 3.97 (dd, J = 9.5, 4.3 Hz, 2H), 3.42 (td, J = 11.9, 1.9 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 2.90 (tq, J = 7.1, 3.7 Hz, 1H), 2.50 (s, 3H), 1.89-2.02 (m, 1H), 1.76 (d, J = 13.1 Hz, 2H), 1.64 (br, s, 1H), 1.50-1.37 (m, 2H), 0.92-0.84 (m, 2H), 0.65- 0.58 (m, 2H).

C70 [C₂₈H₃₄N₈O + H]⁺ 499.3; 499.2 free base; 97.4% at 254 nm (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 7.96 (s, 1H), 7.85 (dd, J = 8.2, 1.1 Hz, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.13-5.98 (m, 2H), 4.99-4.91 (m, 2H), 4.22 (d, J = 5.8 Hz, 1H), 4.08 (t, J = 6.7 Hz, 2H), 3.21 (q, J = 6.5 Hz, 2H), 2.90 (tq, J = 7.1, 3.6 Hz, 1H), 2.50 (s, 3H), 2.20-2.07 (m, 4H), 1.82-1.60 (m, 4H), 1.54 (dq, J = 12.7, 6.6 Hz, 2H), 0.90-0.82 (m, 2H), 0.65- 0.57 (m, 2H).

C71 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.4 free base; 98.2% at 254 nm (400 MHz, DMSO-d₆) δ ppm 8.33 (s, 1H), 8.17 (d, J = 4.3 Hz, 1H), 8.01-7.97 (m, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 5.5 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 5.4 Hz, 1H), 5.33 (s, 1H), 4.67 (dd, J = 7.7, 5.9 Hz, 2H), 4.39 (t, J = 5.9 Hz, 2H), 3.85 (dd, J = 10.7, 2.9 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 3.30- 3.22 (m, 3H), 3.12 (t, J = 6.5 Hz, 2H), 2.85- 2.76 (m, 1H), 2.36 (s, 3H), 2.00-1.86 (m, 1H), 1.60(d, J = 12.0 Hz, 2H), 1.30-1.16 (m, 2H), 0.69-0.62 (m, 2H), 0.52 (m, 2H).

C72 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4 free base; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 8.09 (s, 1H), 7.88 (dd, J = 8.2, 1.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 4.37-4.27 (m, 1H), 3.90 (td, J = 8.2, 5.4 Hz, 1H), 3.82 (dd, J = 8.8, 6.8 Hz, 1H), 3.70-3.77 (m, 1H), 3.62 (dd, J = 8.8, 5.0 Hz, 1H), 3.24 (d, J = 7.3 Hz, 2H), 2.88-2.81 (m, 1H), 2.71-2.58 (m, 1H), 2.43 (s, 3H), 2.18-2.04 (m, 3H), 1.84-1.49 (m, 7H), 0.85-0.77 (m, 2H), 0.65-0.59 (m, 2H).

C73 [C₂₉H₃₃N₇O₃ + H]⁺ 512.3; 512.4 free base; 97.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.51 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 7.83 (s, 1H), 7.71-7.79 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.30-7.24 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.44 (s, 1H), 4.77 (s, 2H), 3.94 (dd, J = 11.0, 3.8 Hz, 2H), 3.37 (d, J = 12.0 Hz, 2H), 3.23-3.14 (m, 2H), 2.84 (tt, J = 7.3, 3.8 Hz, 1H), 2.34 (s, 3H), 2.00-1.87 (m, 1H), 1.75-1.64 (m, 2H), 1.41-1.26 (m, 2H), 0.84-0.76 (m, 2H), 0.66- 0.57 (m, 2H).

C74 [C₂₉H₃₃N₇O₂ + H]⁺ 512.3; 512.4 free base; 98.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.64 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 8.18 (s, 1H), 7.91 (dt, J = 7.9, 1.8 Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J = 8.2, 1.6 Hz, 1H), 7.39 (dd, J = 8.4, 4.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.40 (s, 1H), 4.71 (s, 2H), 3.96 (dd, J = 11.0, 3.5 Hz, 2H), 3.41 (td, J = 11.9, 1.9 Hz, 2H), 3.21 (d, J = 7.0 Hz, 2H), 2.84 (tt, J = 7.4, 3.8 Hz, 1H), 2.38 (s, 3H), 2.05-1.91 (m, 1H), 1.77-1.69 (m, 2H), 1.44-1.30 (m, 2H), 0.85- 0.77 (m, 2H), 0.65-0.60 (m, 2H).

C75 [C₂₉H₃₄N₈O₂ + H]⁺ 527.3; 527.4 free base; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.64 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 5.0, 1.5 Hz, 1H), 8.19 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J = 8.0, 1.5 Hz, 1H), 7.38 (dd, J = 7.9, 4.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 4.71 (s, 2H), 3.74 (t, J = 4.6 Hz, 4H), 3.45 (t, J = 6.4 Hz, 2H), 2.85 (tt, J = 7.4, 3.8 Hz, 1H), 2.77 (t, J = 6.1 Hz, 2H), 2.61 (br, s, 4H), 2.38 (s, 3H), 0.85-0.78 (m, 2H), 0.66-0.59 (m, 2H).

C76 [C₂₇H₃₅N₇O₂ + H]⁺ 490.3; 490.4 free base; 97.9% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.03 (s, 1H), 7.92 (dd, J = 8.2, 1.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.38-5.34 (m, 1H), 3.71-3.78 (m, 4H), 3.48-3.40 (m, 2H), 3.36-3.33 (m, 2H), 2.86 (tt, J = 7.4, 3.8 Hz, 1H), 2.70-2.75 (m, 2H), 2.60-2.52 (m, 4H), 2.45 (s, 3H), 1.26-1.15 (m, 1H), 0.86-0.78 (m, 2H), 0.66-0.60 (m, 2H), 0.58-0.52 (m, 2H), 0.35- 0.29 (m, 2H).

C77 [C₂₈H₃₇N₇O₂ + H]⁺ 504.3; 504.4 free base; 95.9% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.10 (s, 1H), 7.90 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.33 (s, 1H), 4.35 (quint, J = 6.5 Hz, 1H), 3.76-3.71 (m, 4H), 3.42 (t, J = 6.4 Hz, 2H), 2.85 (tt, J = 7.3, 3.8 Hz, 1H), 2.71 (t, J = 6.4 Hz, 2H), 2.52-2.58 (m, 4H), 2.45 (br, s, 3H), 2.20- 2.08 (m, 2H), 1.86-1.51 (m, 6H), 0.86-0.78 (m, 2H), 0.66-0.60 (m, 2H).

C78 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.4 free base; 99.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 8.10 (s, 1H), 7.86 (dd, J = 8.2, 1.6 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 5.50 (s, 1H), 4.31 (br, s, 1H), 4.01-3.92 (m, 3H), 3.59 (dd, J = 11.2, 8.4 Hz, 1H), 3.44 (td, J = 11.8, 1.8 Hz, 2H), 3.26-3.20 (m, 2H), 2.86 (tt, J = 7.4, 3.8 Hz, 1H), 2.47 (s, 3H), 2.08-1.96 (m, 1H), 1.80-1.73 (m, 2H), 1.46-1.32 (m, 2H), 1.07 (s, 9H), 0.85-0.79 (m, 2H), 0.66-0.60 (m, 2H).

C79 [C₂₈H₃₆N₆O₄ + H]⁺ 521.3; 521.3 free base; 98.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 8.04-8.02 (m, 1H), 7.89 (dd, J = 8.2, 1.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 5.42 (d, J = 1.5 Hz, 1H), 4.26 (dd, J = 11.0, 4.8 Hz, 1H), 4.09-4.01 (m, 1H), 4.01-3.95 (m, 3H), 3.76 (td, J = 9.2, 4.8 Hz, 1H), 3.52 (td, J = 11.2, 2.5 Hz, 1H), 3.43 (t, J = 11.4 Hz, 2H), 3.26- 3.20 (m, 3H), 2.89-2.81 (m, 1H), 2.46 (s, 3H), 2.12-1.97 (m, 2H), 1.79-1.66 (m, 3H), 1.46-1.33 (m, 2H), 0.85-0.79 (m, 2H), 0.66-0.60 (m, 2H).

C80 [C₂₅H₃₂N₆O₂ + H]⁺ 449.3; 449.3 free base; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.38-5.32 (m, 1H), 4.39-4.28 (m, 1H), 3.70- 3.62 (m, 2H), 3.52-3.44 (m, 2H), 3.42 (s, 3H), 2.85 (tt, J = 7.3, 3.9 Hz, 1H), 2.44 (s, 3H), 2.15-2.09 (m, 2H), 1.85-1.53 (m, 6H), 0.86-0.77 (m, 2H), 0.66- 0.59 (m, 2H).

C81 [C₂₄H₃₀N₆O₂ + H]⁺ 435.2; 435.3 free base; 99.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.34 (quint, J = 6.6 Hz, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.85 (tt, J = 7.3, 3.8 Hz, 1H), 2.44 (s, 3H), 2.18-2.07 (m, 2H), 1.86-1.51 (m, 6H), 0.85- 0.77 (m, 2H), 0.66-0.59 (m, 2H).

C82 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 free base; 99.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 8.05 (s, 1H), 7.91 (dd, J = 8.3, 1.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 4.12-4.20 (m, 2H), 3.94- 4.01 (m, 2H), 3.80-3.88 (m, 1H), 3.49-3.58 (m, 1H), 3.43 (td, J = 11.7, 1.6 Hz, 2H), 3.33-3.37 (m, 1H), 3.21 (d, J = 7.0 Hz, 2H), 2.80-2.90 (m, 1H), 2.45 (s, 3H), 2.09-2.17 (m, 1H), 1.93-2.07 (m, 1H), 1.81-1.90 (m, 1H), 1.61-1.79 (m, 4H), 1.38 (qd, J = 12.3, 4.4 Hz, 2H), 0.78-0.85 (m, 2H), 0.60-0.66 (m, 2H).

C83 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 free base: 99.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 8.05 (s, 1H), 7.91 (dd, J = 8.3, 1.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 4.12-4.20 (m, 2H), 3.94- 4.01 (m, 2H), 3.80-3.88 (m, 1H), 3.49-3.58 (m, 1H), 3.43 (td, J = 11.7, 1.6 Hz, 2H), 3.33-3.37 (m, 1H), 3.21 (d, J = 7.0 Hz, 2H), 2.80-2.90 (m, 1H), 2.45 (s, 3H), 2.09-2.17 (m, 1H), 1.93-2.07 (m, 1H), 1.81-1.90 (m, 1H), 1.61-1.79 (m, 4H), 1.38 (qd, J = 12.3, 4.4 Hz, 2H), 0.78-0.85 (m, 2H), 0.60-0.66 (m, 2H).

C84 [C₂₉H₃₇N₇O₃ + H]⁺ 532.3; 532.4 free base; 97.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.26 (s, 1H), 7.96-7.91 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 5.60 (s, 1H), 3.97 (dd, J = 11.2, 3.4 Hz, 2H), 3.83-3.76 (m, 2H), 3.71 (s, 4H), 3.70-3.66 (m, 2H), 3.43 (td, J = 11.8, 2.0 Hz, 2H), 3.29 (d, J = 7.0 Hz, 2H), 2.86 (tt, J = 7.3, 3.7 Hz, 1H), 2.45 (s, 3H), 2.17 (s, 3H), 2.06- 1.93 (m, 1H), 1.76 (dd, J = 12.7, 1.6 Hz, 2H), 1.40 (qd, J = 12.4, 4.4 Hz, 2H), 0.86-0.79 (m, 2H), 0.66-0.60 (m, 2H).

C85 [C₃₀H₃₄N₆O₄ + H]⁺ 543.3; 543.4 free base; 98.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.34 (s, 1H), 7.87 (s, 1H), 7.64 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.92-6.78 (m, 3H), 5.78 (s, 1H), 3.81 (s, 3H), 3.76-3.69 (m, 4H), 3.51 (s, 2H), 2.83 (tt, J = 7.4, 3.8 Hz, 1H), 2.71 (t, J = 6.4 Hz, 2H), 2.55 (br, s, 4H), 2.28 (s, 3H), 0.84- 0.77 (m, 2H), 0.63-0.57 (m, 2H).

C86 [C₃₀H₃₄N₆O₅S + H]⁺ 591.2; 591.4 free base; 97.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.40-8.36 (m, 1H), 7.93-7.88 (m, 2H), 7.80-7.70 (m, 2H), 7.69-7.62 (m, 2H), 7.20 (d, J = 7.8 Hz, 1H), 5.96 (s, 1H), 3.76 (m, J = 4.5 Hz, 4H), 3.60 (t, J = 6.4 Hz, 2H), 3.16 (s, 3H), 2.86-2.80 (m, 1H), 2.78 (t, J = 6.3 Hz, 2H), 2.64-2.56 (m, 4H), 2.26 (s, 3H), 0.84-0.77 (m, 2H), 0.63-0.57 (m, 2H).

C87 [C₂₈H₃₄N₆O₄ + H]⁺ 521.3; 521.4 free base; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.25 (s, 1H), 7.98-7.90 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 5.60 (s, 1H), 4.38-4.29 (m, 1H), 4.26-4.17 (m, 2H), 4.05-3.92 (m, 4H), 3.76-3.59 (m, 3H), 3.44 (td, J = 11.8, 2.0 Hz, 2H), 3.31-3.28 (m, 2H), 3.28-3.22 (m, 1H), 2.85 (tt, J = 7.4, 3.8 Hz, 1H), 2.45 (s, 3H), 2.08- 1.94 (m, 1H), 1.81-1.73 (m, 2H), 1.47-1.34 (m, 2H), 0.86-0.78 (m, 2H), 0.65-0.59 (m, 2H).

C88 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3; 535.5 free base; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 7.90 (s, 1H), 7.73 (dd, J = 8.2, 1.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.56-5.54 (m, 1H), 4.02-3.96 (m, 4H), 3.81-3.76 (m, 3H), 3.50-3.41 (m, 2H), 3.35-3.30 (m, 2H), 3.25 (d, J = 6.8 Hz, 2H), 2.90-2.82 (m, 1H), 2.44 (s, 3H), 2.42-2.38 (m, 1H), 2.10-1.98 (m, 1H), 1.89-1.72 (m, 4H), 1.47-1.34 (m, 2H), 0.85- 0.79 (m, 2H), 0.65-0.60 (m, 2H).

C89 [C₃₀H₄₀N₆O₄ + H]⁺ 549.3; 549.5 free base; 98.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.01 (s, 1H), 7.92-7.83 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.34 (s, 1H), 4.23-4.08 (m, 1H), 4.00-43.68 (m, 6H), 3.46-3.22 (m, 4H), 3.05 (d, J = 7.0 Hz, 2H), 2.84 (tt, J = 7.3, 3.7 Hz, 1H), 2.44 (s, 3H), 2.08- 1.96 (m, 1H), 1.90-1.69 (m, 3H), 1.67-1.42 (m, 4H), 1.35-1.13 (m, 2H), 0.84-0.76 (m, 2H), 0.65- 0.57 (m, 2H).

C90 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3; 535.5 free base; 98.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.92-7.99 (m, 2H), 7.29 (d, J = 8.5 Hz, 1H), 5.36 (s, 1H), 4.62 (br. s., 1H), 4.17 (dd, J = 9.3, 5.3 Hz, 1H), 4.06- 3.98 (m, 2H), 3.95 (dd, J = 11.2, 3.4 Hz, 2H), 3.85- 3.73 (m, 3H), 3.57 (dq, J = 9.3, 7.0 Hz, 1H), 3.40 (td, J = 11.8, 2.0 Hz, 2H), 3.18 (d, J = 7.0 Hz, 2H), 2.90-2.81 (m, 1H), 2.45 (s, 3H), 2.01-1.88 (m, 1H), 1.76-1.65 (m, 2H), 1.35 (qd, J = 12.5, 4.5 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H), 0.87-0.77 (m, 2H), 0.66- 0.60 (m, 2H).

C91 [C₃₃H₃₉N₇O₄ + H]⁺ 598.3; 598.4 free base; 98.5% at 254 nm (400 MHz, CDCl₃) δ ppm 8.27 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.37-7.30 (m, 1H), 7.27-7.24 (m, 1H), 6.87-6.78 (m, 4H), 5.62 (s, 1H), 3.88-3.82 (m, 4H), 3.82-3.75 (m, 4H), 3.48-3.41 (m, 2H), 3.22-3.15 (m, 4H), 2.93-2.85 (s, 1H), 2.78 (t, J = 5.9 Hz, 2H), 2.56 (br. s., 4H), 2.38 (s, 3H), 1.59-1.55 (m, 1H), 0.91-0.83 (m, 2H), 0.64-0.56 (m, 2H).

C92 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.4 free base; 99.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 7.90 (dd, J = 8.0, 1.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.45 (s, 1H), 4.39-4.29 (m, 1H), 3.79- 3.67 (m, 4H), 3.65 (s, 2H), 3.37 (s, 2H), 2.85 (tt, J = 7.3, 3.8 Hz, 1H), 2.44 (s, 3H), 2.19-2.09 (m, 2H), 1.86-1.74 (m, 2H), 1.74-1.53 (m, 8H), 0.86- 0.78 (m, 2H), 0.67-0.59 (m, 2H).

C93 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3; 535.4 free base; 98.7% at 254 nm NMR (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.10 (s, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 5.47 (s, 1H), 4.25-4.14 (m, 1H), 4.08- 4.00 (m, 2H), 3.79-3.69 (m, 4H), 3.68-3.65 (m, 2H), 3.62 (td, J = 11.7, 2.3 Hz, 2H), 3.39 (s, 2H), 2.89-2.82 (m, 1H), 2.45 (s, 3H), 2.19-2.10 (m, 2H), 1.69-1.56 (m, 6H), 0.85-0.78 (m, 2H), 0.66-0.61 (m, 2H).

C94 [C₂₈H₃₆N₆O₄ + H]⁺ 521.3; 521.4 free base; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 8.10 (s, 1H), 7.88-7.83 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.42 (s, 1H), 4.25-4.13 (m, 1H), 4.08-3.99 (m, 2H), 3.86-3.72 (m, 4H), 3.61 (td, J = 11.6, 1.9 Hz, 2H), 3.35-3.28 (m, 2H), 2.91-2.80 (m, 1H), 2.45 (s, 3H), 2.19-2.09 (m, 2H), 1.84-1.73 (m, 2H), 1.69- 1.55 (m, 4H), 0.86-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C95 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 free base; 99.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, H), 8.09 (s, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 4.34 (quin, J = 6.7 Hz, 1H), 3.87-3.72 (m, 4H), 3.35-3.27 (m, 2H), 2.91- 2.81 (m, 1H), 2.44 (s, 3H), 2.20-2.08 (m, 2H), 1.87-1.51 (m, 10H), 0.86-0.77 (m, 2H), 0.67- 0.60 (m, 2H).

C96 [C₃₁H₃₇N₇O₃ + H]⁺ 556.3; 556.5 free base; 95.2% at 254 nm (400 MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.90 (s, 1H), 7.71-7.65 (m, 1H), 7.28 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.72-6.63 (m, 2H), 6.58 (dd, J = 7.8, 1.8 Hz, 1H), 5.75 (s, 1H), 3.77-3.70 (m, 4H), 3.51 (t, J = 6.3 Hz, 2H), 2.96 (s, 6H), 2.84 (tt, J = 7.4, 3.7 Hz, 1H), 2.71 (t, J = 6.4 Hz, 2H), 2.55 (br. s., 4H), 2.29 (s, 3H), 0.85-0.76 (m, 2H), 0.64-0.58 (m, 2H).

C97 [C₂₉H₃₁ClN₆O₃ + H]⁺ 547.2; 547.3 free base; 95.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.40-7.49 (m, 1H), 7.37 (t, J = 2.1 Hz, 1H), 7.34-7.27 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 5.86 (s, 1H), 3.75 (t, J = 4.5 Hz, 4H), 3.57 (t, J = 6.4 Hz, 2H), 2.88-2.80 (m, 1H), 2.77 (t, J = 6.4 Hz, 2H), 2.59 (br. s., 4H), 2.29 (s, 3H), 0.77-0.83 (s, 2H), 0.57-0.64 (m, 2H).

C98 [C₂₈H₃₀N₆O₄ + H]⁺ 515.2; 515.3 free base; 97.7% at 254 nm NMR (400 MHz, CD₃OD) δ ppm 8.55 (d, J = 2.8 Hz, 1H), 8.48 (dd, J = 4.8, 1.3 Hz, 1H), 8.36 (s, 1H), 7.86-7.80 (m, 1H), 7.73 (s, 1H), 7.62-7.54 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 3.87- 3.74 (m, 4H), 3.47 (s, 2H), 2.89-2.77 (m, 1H), 2.26 (s, 3H), 1.87-1.75 (m, 2H), 1.72-1.61 (m, 2H), 0.84-0.76 (m, 2H), 0.65-0.56 (m, 2H).

C99 [C₂₉H₃₂N₆O₄ + H]⁺ 529.3; 529.4 free base; 97.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.57 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 4.8, 1.3 Hz, 1H), 8.36 (s, 1H), 7.87-7.83 (m, 1H), 7.75 (s, 1H), 7.62-7.57 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 3.82-3.68 (m, 6H), 3.54 (s, 2H), 2.87-2.79 (m, 1H), 2.26 (s, 3H), 1.63-1.66 (m, 4H), 0.82-0.78 (m, 2H), 0.63- 0.58 (m, 2H).

C100 [C₂₆H₂₆N₆O₃ + H]⁺ 471.2 471.1; free base; 91.9% at 254 nm (400 MHz, CDCl₃ + drops of CD₃OD) δ ppm 8.58 (br. s., 1H), 8.49 (br. s., 1H), 8.22 (s, 1H), 7.73- 7.61 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.46-7.39 (m, 1H), 7.21 (d, J = 8.8 Hz, 1H), 5.76 (s, 1H), 4.93 (t, J = 6.4 Hz, 2H), 4.50 (t, J = 5.8 Hz, 2H), 3.76 (d, J = 6.5 Hz, 2H), 3.41 (d, J = 11.5 Hz, 1H), 2.85 (br. s., 1H), 2.31 (br. s., 3H), 0.94-0.82 (m, 2H), 0.62- 0.53 (m, 2H);

C101 [C₂₈H₃₂N₆O₄ + H]⁺ 493.2; 493.3 free base; 94% at 254 nm (400 MHz, CDCl₃) δ ppm 8.24 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 4.8 Hz, 1H), 5.95 (br. s., 1H), 5.74 (quint, J = 5.9 Hz, 1H), 5.50 (s, 1H), 5.07 (t, J = 7.2 Hz, 2H), 4.83 (dd, J = 7.8, 5.5 Hz, 2H), 3.82- 3.73 (m, 4H), 3.45-3.38 (m, 2H), 2.97-2.87 (m, 1H), 2.76 (t, J = 6.0 Hz, 2H), 2.59-2.50 (s, 7H), 0.94-0.85 (m, 2H), 0.63 (m, 2H);

C102 [C₂₆H₃₂N₆O₃ + H]⁺ 477.3; 477.3 free base; 93% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 5.14 (m, 1H), 5.07-5.00 (m, 2H), 4.68 (t, J = 6.4 Hz, 2H), 3.98 (dd, J = 11.3, 3.3 Hz, 2H), 3.43 (td, J = 11.7, 1.9 Hz, 2H), 3.23 (d, J = 7.0 Hz, 2H), 2.86 (tt, J= 7.3, 3.8 Hz, 1H), 2.47 (s, 3H), 2.06-1.95 (m, 1H), 1.75 (d, J = 12.8 Hz, 2H), 1.46-1.32 (m, 2H), 0.85-0.76 (m, 2H), 0.66-0.60 (m, 2H).

C103 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.6; HCl salt; 98.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.47 (s, 1H), 7.45-7.39 (m, 2H), 5.54 (s, 1H), 3.98 (dd, J = 11.0, 3.0 Hz, 2H), 3.50-3.43 (m, 4H), 2.92-2.87 (m, 1H), 2.48 (s, 3H), 2.08 (s, br, 1H), 1.80-1.73 (m, 2H), 1.50-1.37 (m, 2H), 0.87-0.81 (m, 2H), 0.71- 0.63 (m, 4H), 0.43-0.37 (m, 2H).

C104 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.3 TFA salt; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 7.55-7.37 (m, 3H), 5.67 (s, 1H), 3.98 (dd, J = 11.6, 3.6 Hz, 2H), 3.87 (s, br, 1H), 3.69-3.57 (m, 2H), 3.47-3.33 (m, 7H), 2.91-2.85 (m, 1H), 2.46 (s, 3H), 2.12-1.98 (m, 2H), 1.77-1.70 (m, 2H), 1.48-1.35 (m, 2H), 1.10-1.04 (m, 6H), 0.85-0.80 (m, 2H), 0.66-0.61 (m, 2H),

C105 [C₂₈H₂₉ClN₆O₃ + H]⁺ 533.2; 533.2 TFA salt; 99.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.27 (s, 1H), 7.96 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.29-7.22 (m, 4H), 5.89 (s, 1H), 4.15-3.80 (m, 6H), 3.80-3.50 (m, 4H), 3.35-3.15 (m, 2H), 2.89- 2.82 (m, 1H), 0.84-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C106 [C₃₁H₃₆N₆O₃ + H]⁺ 541.3; 541.3 TFA salt; 96.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.40 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.33-7.27 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 4.07 (s, 2H), 4.06-3.98 (m, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.32 (quint, J = 1.6 Hz, 1H), 2.94 (s, 6H), 2.87-2.79 (m, 1H), 2.25 (s, 3H), 2.27- 2.01 (m, 2H), 0.83-0.77 (m, 2H), 0.63-0.58 (m, 2H).

C107 [C₂₇H₃₄N₆O₄ + H]⁺ 507.3; 507.2 TFA salt; 98.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.48 (s, 1H), 7.46-7.37 (m, 2H), 5.62 (s, 1H), 4.55-4.50 (m, 1H), 4.41 (q, J = 6.0 Hz, 1H), 4.21 (dd, J = 8.4, 7.2 Hz, 1H), 4.07 (dd, J = 10.0, 4.8 Hz, 1H), 3.99 (dd, J = 11.4, 7.4 Hz, 2H), 3.83 (dd, J = 9.8, 2.6 Hz, 1H), 3.73-3.67 (m, 1H), 3.50-3.40 (m, 4H), 2.92-2.86 (m, 1H), 2.46 (s, 3H), 2.13-2.01 (m, 1H), 1.78-1.72 (m, 2H), 1.50-1.38 (m, 2H), 0.86-0.81 (m, 2H), 0.67-0.61 (m, 2H).

C108 [C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.2 TFA salt; 98.9% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.47 (s, 1H), 7.46-7.40 (m, 2H), 5.73 (s, 1H), 4.05-3.98 (m, 1H), 3.95-3.83 (m, 1H), 3.77-3.68 (m, 4H), 3.42 (s, 3H), 2.92-2.87 (m, 1H), 2.47 (s, 3H), 1.90-1.67 (m, 6H), 1.60-1.43 (m, 2H), 0.87-0.81 (m, 2H), 0.66- 0.62 (m, 2H).

C109 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.2 TFA salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.45 (s, 1H), 7.43-7.38 (m, 2H), 5.41 (s, 1H), 4.30 (quint, J = 7.90, 1H), 3.98 (dd, J = 11.6. 3.2 Hz, 2H), 3.49- 3.40 (m, 4H), 2.92-2.87 (m, 1H), 2.46 (s, 3H), 2.17-2.00 (m, 3H), 1.96-1.87 (m, 2H), 1.78-1.72 (m, 2H), 1.49-1.38 (m, 2H), 0.86-0.81 (m, 2H), 0.67-0.62 (m, 2H).

C110 [C₂₆H₃₄N₆O₄ + H]⁺ 495.3; 495.3 HCl salt; 97.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.55-7.30 (m, 3H), 5.74 (s, 1H), 4.10-3.65 (m, 7H), 3.55-3.25 (m, 4H), 2.93-2.83 (m, 1H), 2.46 (s, 3H), 2.20-2.04 (m, 1H), 1.85-1.65 (m, 2H), 1.55-1.30 (m, 2H), 0.85-0.75 (m, 2H), 0.70-0.58 (m, 2H).

C111 [C₂₈H₃₇N₇O₃ + H]⁺ 520.3; 520.3 HCl salt; 98.7% at 254 nm (400 MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.60-7.30 (m, 3H), 5.46 (s, 1H), 4.40-3.85 (m, 3H), 3.75-3.25 (m, 4H), 2.92-2.84 (m, 1H), 2.46 (s, 3H), 2.40-2.25 (m, 1H), 2.20-1.98 (m, 1H), 1.85-1.65 (m, 2H), 1.60-1.35 (m, 2H), 1.25-1.00 (m, 6H), 0.85-0.75 (m, 2H), 0.70-0.58 (m, 2H).

C112 [C₂₉H₃₆N₆O₃ + H]⁺ 517.3; 517.3 HCl salt; 97.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.15 (s, 1H), 7.52-7.33 (m, 3H), 4.70-4.55 (m, 2H), 4.05-3.65 (m, 6H), 3.55-3.47 (m, 4H), 2.92-2.82 (m, 1H), 2.55 (s, 3H), 2.30-2.00 (m, 5H), 1.85-1.73 (m, 2H), 1.55-1.37 (m, 2H). 0.86-0.80 (m, 2H), 0.65-0.60 (m, 2H).

C113 C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3 HCl salt; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 7.53-7.35 (m, 3H), 3.98 (s, 2H), 3.65-3.30 (m, 8H), 2.92-2.84 (m, 1H), 2.47 (s, 3H), 2.20-2.05 (m, 1H), 1.85-1.67 (m, 2H), 1.52-1.38 (m, 2H), 0.85-0.78 (m, 2H), 0.72-0.52 (m, 6H).

C114 [C₂₉H₃₉N₇O₃ + H]⁺ 534.3; 534.6 free base; 99.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 7.98-7.94 (m, 2H), 7.30 (d, J = 1.6 Hz, 1H), 5.37 (s, 1H), 4.00-3.96 (m, 2H), 3.73-3.71 (m, 4H), 3.66 (t, J = 6.8 Hz, 2H), 3.43 (t, J = 9.6 Hz, 2H), 3.24 (d, J = 6.8 Hz, 2H), 2.87-2.84 (m, 1H), 2.71-2.68 (m, 2H), 2.59 (s, 4H), 2.45 (s, 3H), 2.03-2.00 (m, 1H), 1.77- 1.75 (m, 2H), 1.45-1.35 (m, 2H), 0.84-0.79 (m, 2H), 0.64-0.60 (m, 2H).

C115 [C₃₁H₄₀N₆O₄ + H]⁺ 562.3; 562.3; free base; 96.8% at 254 nM (400 MHz, CD₃OD) δ ppm 8.31 (s, 1H), 8.00 (s, 1H), 7.86-7.84 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 5.22-5.21 (m, 1H), 4.72-4.67 (m, 2H), 4.63-4.59 (m, 2H), 3.97-3.94 (m, 2H), 3.55-3.50 (m, 1H), 3.44-3.41 (m, 2H), 3.27-3.23 (m, 2H), 2.88-2.84 (m, 1H), 2.73-2.63 (m, 2H), 2.44 (s, 3H), 2.26-2.17 (m, 9H), 1.74-1.71 (m, 2H), 1.42-1.32 (m, 2H), 0.84-0.79 (m, 2H), 0.65-0.61 (m, 2H).

C116 [C₃₀H₃₈N₆O₄ + H]⁺ 547.3; 547.6; TFA salt; 96.7% at 254 nM (400 MHz, CD₃OD) δ ppm 8.36 (s, 1H), 7.93-7.88 (m, 2 H), 7.34 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 5.67 (s, 1H), 4.97-4.92 (m, 3H), 4.77-4.74 (m, 2H), 4.63-4.59 (m, 1H), 3.96-3.65 (m, 7H), 3.56-3.45 (m, 3H), 2.89-2.84 (m, 1H), 2.68-2.66 (m, 1H), 2.46 (s, 3H), 2.06-1.98 (m, 1H), 1.76-1.73 (m, 2H), 1.45-1.35 (m, 2H), 0.85-0.80 (m, 2H), 0.65-0.61 (m, 2H).

C117 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3 535.3 TFA salt; 97.6% at 254 nM (400 MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.93-7.89 (m, 2H), 7.34 (d, J = 8.0 Hz. 1H), 5.69 (s, 1H), 4.91-4.88 (m, 2H), 4.86 (t, J = 4.8 Hz, 2H), 4.03- 3.96 (m, 4H), 3.79-3.76 (m, 2H), 3.72-3.65 (m, 4H), 3.45-3.40 (m, 2H), 3.30-3.38 (m, 2H), 2.89- 2.84 (m, 1H), 2.46 (s, 3H), 2.06-1.99 (m, 1H), 1.76-1.73 (m, 2H), 1.45-1.35 (m, 2H), 0.85-0.80 (m, 2H), 0.65-0.61 (m, 2H).

C118 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3; TFA salt; 98.9% at 254 nM (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.47 (s, 1H), 7.43 (m, 2H), 5.69 (s, 1H), 4.01-3.95 (m, 4H), 3.47-3.41 (m, 4H), 2.91-2.85 (m, 1H), 2.47 (s, 3H), 2.10-2.04 (m, 1H), 1.82-1.69 (m, 8H), 1.56-1.37 (m, 4H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C119 [C₂₈H₃₉N₇O₃ + H]⁺ 522.3; 522.3; free base; 95% at 254 nM (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 4.04-3.97 (m, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3.46-3.42 (m, 2H), 2.88-2.82 (m, 1H), 2.74-2.70 (m, 2H), 2.56 (br.s, 4H), 2.45 (s, 3H), 1.81-1.73 (m, 1H), 1.7-1.61 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 8.0 Hz, 3H), 0.84-0.79 (m, 2H), 0.64-0.60 (m, 2H).

C120 [C₃₀H₃₉N₇O₃ + H]⁺ 547.3; 547.3; di-TFA salt; 98.7% at 254 nM (400 MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.81-7.65 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 4.93-4.85 (m, 2H), 4.81-4.75 (m, 1H), 4.74-4.70 (m, 2H), 4.60- 4.54 (m, 1H), 4.00-3.96 (m, 3H), 3.79-3.70 (m, 3H), 3.53-3.40 (m, 3H), 3.36-3.31 (m, 2H), 2.87- 2.84 (m, 1H), 2.69-2.60 (m, 1H), 2.46 (s, 3H), 2.32-2.24 (m, 1H), 2.08-1.99 (m, 1H), 1.77-1.74 (m, 2H), 1.46-1.35 (m, 2H), 0.85-0.80 (m, 2H), 0.64-0.61 (m, 2H).

C121 [C₂₈H₃₈N₆O₃ + H]⁺ 507.3; 507.3; TFA salt: 99.5% at 254 nM (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 5.70 (s, 1H), 4.00-3.97 (m, 2H), 3.85-3.67 (m, 3H), 3.46-3.41 (m, 4H), 2.91- 2.85 (m, 1H), 2.47 (s, 3H), 2.11-2.02 (m, 2H), 1.76-1.73 (m, 2H), 1.47-1.77 (m, 2H), 1.08 (t, J = 6.8 Hz, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C122 [C₃₁H₄₁N₇O₃ + H]⁺ 560.3; 560.3; di-TFA salt; 99.9% at 254 nM (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.61-7.58 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 4.90-4.83 (m, 5H), 4.48-4.45 (m, 1H), 4.19-4.15 (m, 1H), 4.00- 3.96 (m, 2H), 3.65-3.43 (m, 6H), 3.14-3.06 (m, 2H), 2.90-2.86 (m, 1H), 2.45-2.36 (m, 5H), 2.10- 1.92 (m, 3H), 1.77-1.74 (m, 2H), 1.47-1.37 (m, 2H), 0.85-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C123 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; TFA salt; 97.1% at 254 nM (400 MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.50 (s, 1H), 7.46-7.40 (m, 2H), 5.58 (s, 1H), 4.10-4.05 (m, 1H), 4.00-3.97 (m, 2H), 3.91-3.86 (m, 1H), 3.46- 3.38 (m, 4 H), 2.87-2.85 (m, 1H), 2.46 (s, 3H), 2.31-2.24 (m, 1H), 2.12-2.06 (m, 2H), 1.94-1.69 (m, 6H), 1.46-1.36 (m, 2H), 0.86-0.81 (m, 2H), 0.65-0.61 (m,2H).

C124 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3; TFA salt; 99.5% at 254 nM (400 MHz, CD₃OD) δ ppm 8.24 (s, 1H), 7.51 (s, 1H), 7.46-7.41 (m, 2H), 5.64 (s, 1 H), 3.98 (dd, J = 11.2, 3.2 Hz, 2H), 3.53 (m, 2H), 3.46-3.38 (m, 4H), 2.90-2.85 (m, 1H), 2.47 (s, 3H), 2.12-2.03 (m, 3H), 1.81-1.73 (m, 4H), 1.47-1.34 (m, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C125 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3; TFA salt; 99.1% at 254 nM (400 MHz, CD₃OD) δ ppm 8.24 (s, 1H), 7.52 (s, 1H), 7.46-7.42 (m, 2H), 5.64 (s, 1H), 4.00-3.97 (m, 2H), 3.53 (m, 2H), 3.46-3.35 (m, 4H), 2.90-2.85 (m, 1H), 2.47 (s, 3H), 2.12-2.03 (m, 3H), 1.80-1.73 (m, 4H), 1.54-1.34 (m, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C126 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; free base; 97.6% at 254 nM (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.47 (s, 1H), 7.42 (br. s, 2H), 5.60 (s, 1H), 4.30-4.27 (m, 1H), 4.07-4.02 (m, 1H), 4.00-3.97 (m, 2H), 3.47- 3.41 (m, 4H), 2.89-2.85 (m, 1H), 2.47 (s, 3H), 2.22-2.18 (m, 1H), 2.11-1.91 (m, 3H), 1.82-1.69 (m, 5H), 1.48-1.38 (m, 2H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C127 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.3; free base; 98.9% at 254 nM (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.97 (s, 1H), 7.86 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H), 4.08 (br. s, 1H), 3.98 (dd, J = 11.6, 3.6 Hz, 2H), 3.47-3.43 (m, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.85-2.82 (m, 1H), 2.46 (s, 3H), 2.05-2.00 (m, 1H), 1.99-1.86 (m, 1H), 1.78-1.75 (m, 2H), 1.52-1.34 (m, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H), 0.84-0.79 (m, 2H), 0.64-0.60 (m, 2H).

C128 [C₂₉H₄₂N₆O₃ + H]⁺ 523.3; 523.3; free base; 98.7% at 254 nM (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 3.40-3.34 (m, 3H), 3.30 (s, 3H), 2.88-2.83 (m, 1H), 2.47 (s, 3H), 2.31-2.25 (m, 1H), 1.32 (s, 9H), 1.26 (s, 3H), 1.05 (t, J = 6.4 Hz, 6H), 0.84-0.79 (m, 2H), 0.65-0.61 (m, 2H).

C129 [C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.3; TFA salt; 97.1% at 254 nM (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 5.72 (s, 1H), 4.31-4.28 (m, 1H), 4.05-3.00 (m, 1H), 3.61-3.53 (m, 2H), 3.29 (s, 3H), 2.91-2.85 (m, 1H), 2.47 (s, 3H), 2.23- 2.05 (m, 1H), 2.03-1.93 (m, 2H), 1.82-1.68 (m, 3H), 1.31 (s, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C130 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.3; HCl salt; 98.2% at 254 nM (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.48 (s, 1H), 7.43 (s, 2H), 5.67 (s, 1H), 3.99-3.92 (m, 3H), 3.85-3.74 (m, 1H), 3.69-3.58 (m, 1H), 3.50-3.40 (m, 4H), 2.90-2.85 (m, 1H), 2.47 (s, 3H), 2.13-2.03 (m, 1H), 1.77-1.73 (m, 3H), 1.58-1.38 (m, 4H), 1.03- 0.98 (m, 6H), 0.85-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C131 [C₃₀H₄₀N₆O₃ + H]⁺ 533.3; 533.3; free base; 96.7% at 254 nM (400 MHz, CD₃OD) δ ▭ ppm 8.13 (s, 1H), 7.78- 7.74 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 5.58 (s, 1H), 4.49 (br, s, 1H), 3.97 (dd, J = 10.8, 2.8 Hz, 2H), 3.46-3.43 (m, 2H), 3.43-3.40 (m, 2H), 3.28- 3.21 (m, 2H), 2.87-2.82 (m, 1H), 2.44 (s, 3H), 2.04-2.00 (m, 1H), 1.98-1.80 (m, 2H), 1.77-1.64 (m, 6H), 1.46-1.33 (m, 4H), 1.28-1.22 (m, 1H), 0.84-0.79 (m, 2H). 0.64-0.60 (m, 2H).

C132 [C₂₉H₃₆N₈O₂ + H]⁺ 529.3; 529.2; free base; 96.4% at 254 nM (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.0, 1.2 Hz, 1H), 7.71 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.00 (s, 1H), 5.34 (s, 1H), 4.21-4.14 (m, 4H), ), 3.40-3.29 (m, 2H), 2.88-2.83 (m, 1H), 2.45 (s, 3H), 2.24-2.17 (m, 2H), 1.87-1.64 (m, 6H), 1.49-1.47 (m, 2H), 0.84-0.79 (m, 2H), 0.65-0.61 (m, 2H).

C133 [C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.4; free base; 99.2% at 254 nM (400 MHz, CD₃OD) δ ppm 8.38 (br, s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.89-7.87 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.45 (s, 1H), 4.01-3.91 (m, 3H), 3.88- 3.84 (m, 1H), 3.80-3.68 (m, 1H), 3.68-3.64 (m, 1H), 2.87-2.83 (m, 1H), 2.73-2.70 (m, 1H), 2.45 (s, 3H), 2.16-2.12 (m, 1H), 1.79-1.73 (m, 2H), 1.69-1.63 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H), 0.84-0.79 (m, 2H), 0.64-0.60 (m, 2H).

C134 [C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.4; free base; 95.5% at 254 nM (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.98 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.45 (s, 1H), 4.85-4.95 (m, 2H), 4.00- 3.89 (m, 3H), 3.87-3.85 (m, 1H), 3.80-3.75 (m, 1H), 3.68-3.65 (m, 1H), 2.87-2.83 (m, 1H), 2.73-2.71 (m, 1H), 2.45 (s, 3H), 2.17-2.13 (m, 1H), 1.80-1.74 (m, 2H), 1.69-1.65 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H), 0.84-0.79 (m, 2H), 064-0.60 (m, 2H).

C135 [C₂₈H₃₀N₆O₃ + H]⁺ 499.2; 499.3; free base; 98.9% at 254 nM (400 MHz, CD₃OD) δ ppm 8.55 (dd, J = 2.8, 0.4 Hz, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (s, 1H), 7.83-7.80 (m, 1H), 7.72 (s, 1H), 7.58-7.55 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 3.49 (d, J = 1.6 Hz, 2H), 2.87-2.78 (m, 2H), 2.28- 2.23 (m, 5H), 1.97-1.92 (m, 2H), 1.36 (s, 3H), 0.82-0.77 (m, 2H), 0.62-0.58 (m, 2H).

C136 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.3; TFA salt; 98.2% at 254 nm (400 MHz, CDCl₃) δ ppm 9.35 (br, s, 2H), 7.91 (s, 1H), 7.36-7.28 (m, 1H), 7.25-7.17 (m, 2H), 7.13 (t, J = 5.6 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 5.13 (s, 1H), 4.21 (br, s, 1H), 4.11-3.97 (m, 4H), 3.94-3.86 (m, 1H), 3.80 (dd, J = 9.5, 3.5 Hz, 1H), 3.44 (t, J = 11.2 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 2.97-2.85 (m, 1H), 2.44-2.29 (m, 4H), 2.18-1.97 (m, 2H), 1.76 (d, J = 12.5 Hz, 2H), 1.56-1.37 (m, 2H), 0.95- 0.78 (m, 2H), 0.71-0.57 (in, 2H).

C137 [C₂₇H₃₄N₆O₄ + H]⁺ 507.3; 507.3; TFA salt; 98.8% at 254 nm (400 MHz, CDCl₃) δ ppm 9.33-8.18 (m, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.94 (br, s, 1H), 6.61 (d, J = 2.8 Hz, 1H), 5.46 (br, s, 1H), 5.33 (s, 1H), 4.06-3.84 (m, 7H), 3.83-3.52 (m, 5H), 3.37 (br, s, 2H), 3.15-2.73 (m, 3H), 2.43 (s, 3H), 2.33-2.21 (m, 1H), 2.21-2.09 (m, 1H), 0.97-0.80 (m, 2H), 0.72-0.53 (m, 2H).

C138 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 419.3; TFA salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.58-7.44 (m, 2H), 7.43-7.35 (m, 1H), 4.56-4.44 (m, 1H), 4.08-3.94 (m, 4H), 3.93-3.81 (m, 2H), 3.51-3.38 (m, 4H), 2.94-2.82 (m, 1H), 2.46 (s, 3H), 2.44-2.37 (m, 1H), 2.15-1.97 (m, 2H), 1.76 (d, J = 12.8 Hz, 2H), 1.43 (qd, J = 12.4, 4.4 Hz, 2H), 0.88-0.78 (m, 2H), 0.69-0.58 (m, 2H).

C139 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; TFA salt; 99.2% at 254 nm (400 MHz, CDCl₃) δ ppm 8.95-9.65 (m, 2H), 7.94 (br, s, 1H), 7.44-7.18 (m, 2H), 6.89 (br, s, 2H), 6.59-6.22 (m, 1H), 5.76 (br, s, 1H), 4.03 (br, s, 2H), 3.67 (br, s, 2H), 3.51-3.18 (m, 4H), 2.99-2.81 (m, 1H), 2.42 (br, s, 3H), 2.16-1.88 (m, 1H), 1.82-1.62 (m, 2H), 1.59-1.27 (m, 2H), 1.01 (d, J = 5.0 Hz, 4H), 0.91-0.78 (m, 2H), 0.64 (br, s, 2H).

C140 [C₂₆H₃₄N₆O₄S + H]⁺ 527.2; 527.2; HCl salt: 99.9% at 254 nm (400 MHz, DMSO-d₆) δ ppm 8.42 (br, s, 1 H), 8.22 (br, s, 1 H), 8.08-7.56 (m, 3H), 7.39-7.24 (m, 2H), 7.18 (s, 1H), 7.04 (s, 1H), 5.44 (br, s, 2H), 4.03 (br, s, 1H), 3.96-3.84 (m, 2H), 3.25-3.17 (m, 2H), 2.99 (s, 3H), 2.87-2.74 (m, 1H), 2.37 (s, 3H), 2.13-1.89 (m, 4H), 1.60-1.40 (m, 2H), 0.73-0.61 (m, 2H), 0.59-0.45 (m, 2H).

C141 [C₂₉H₃₆N₆O₃ + H]⁺ 517.3; 517.3; free base; 97.8% at 254 nm (400 MHz, CDCl₃) δ ppm 8.13 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.14 (t, J = 6.0 Hz, 1H), 5.93 (d, J = 2.5 Hz, 1H), 5.06 (s, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.82 (s, 2H), 4.67 (s, 2H), 4.29-4.16 (m, 1H), 4.03 (dd, J = 11.8, 3.3 Hz, 2H), 3.41 (td, J = 11.9, 1.9 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 2.96-2.79 (m, 3H), 2.53 (s, 3H), 2.20-2.09 (m, 2H), 2.01-1.88 (m, 1H), 1.75 (d, J = 11.0 Hz, 2H), 1.50-1.35 (m, 2H), 0.93-0.84 (m, 2H), 0.66-0.58 (m, 2H).

C142 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; HCl salt; 98.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.14 (s, 1H), 7.52-7.38 (m, 3H), 4.64 (br, s, 1H), 3.99 (dd, J = 11.3, 3.8 Hz, 2H), 3.84 (d, J = 7.5 Hz, 3H), 3.65 (d, J = 10.8 Hz, 1H), 3.53-3.39 (m, 4H), 2.94-2.83 (m, 1H), 2.47 (s, 3H), 2.33-2.01 (m, 3H), 1.77 (d, J = 12.3 Hz, 2H), 1.53-1.36 (m, 2H), 0.89-0.79 (m, 2H), 0.72-0.59 (m, 2H).

C143 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; HCl salt; 98.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.14 (s, 1H), 7.52-7.38 (m, 3H), 4.64 (br, s, 1H), 3.99 (dd, J = 11.3, 3.8 Hz, 2H), 3.84 (d, J = 7.5 Hz, 3H), 3.65 (d, J = 10.8 Hz, 1H), 3.53-3.39 (m, 4H), 2.94-2.83 (m, 1H), 2.47 (s, 3H), 2.33-2.01 (m, 3H), 1.77 (d, J = 12.3 Hz, 2H), 1.53-1.36 (m, 2H), 0.89-0.79 (m, 2H), 0.72-0.59 (m, 2H).

C144 [C₂₇H₂₈N₆O₃ + H]⁺ 485.2; 485.3; HCl salt; 98.8% at 254 nm (400 MHz, CD₃OD) δ ppm 9.13 (d, J = 2.3 Hz, 1H), 8.86 (d, J = 5.8 Hz, 1H), 8.77-8.69 (m, 1H), 8.40 (s, 1H), 8.26 (dd, 8.8, 5.8 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H), 4.53-4.39 (m, 1H), 3.57 (d, J = 8.0 Hz, 2H), 2.89-2.79 (m, 1H), 2.76-2.61 (m, 1H), 2.30 (s, 3H), 2.29-2.21 (m, 2H), 2.21-2.08 (m, 2H), 0.85-0.78 (m, 2H), 0.65-0.58 (m, 2H).

C145 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; HCl salt; 97.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 7.52-7.34 (m, 3H), 4.51-4.37 (m, 1H), 4.11-3.91 (m, 3H), 3.73-3.53 (m, 4H), 2.94-2.82 (m, 1H), 2.76-2.59 (m, 1H), 2.48 (s, 3H), 2.30-2.20 (m, 2H), 2.19-2.00 (m, 4H), 1.75-1.58 (m, 2H), 0.90-0.76 (m, 2H), 0.71-0.56 (m, 2H).

C146 [C₂₉H₃₀F₂N₆O₂ + H]⁺ 533.2; 533.7; HCl salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.39 (s, 1H), 7.83 (s, 1H), 7.63 (dd, J = 8.0, 1.5 Hz, 1H), 7.55-7.42 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15-7.03 (m, 3H), 3.79 (d, J = 19.8 Hz, 2H), 3.42 (br, s, 2H), 3.30- 3.18 (m, 2H), 2.91-2.80 (m, 1H), 2.35-2.21 (m, 5H), 2.19-1.96 (m, 2H), 0.87-0.76 (m, 2H), 0.68- 0.58 (m, 2H).

C147 [C₂₉H₃₂FN₇O₂ + H]⁺ 530.3; 530.4; di-HCl salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 9.15 (d, J = 2.5 Hz, 1H), 8.87 (d, J = 5.5 Hz, 1H), 8.79-8.70 (m, 1H), 8.45 (s, 1H), 8.32-8.21 (m, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 3.87 (d, J = 21.8 Hz, 2H), 3.62-3.49 (m, 2H), 3.30-3.23 (m, 1H), 2.94 (s, 3H), 2.89-2.79 (m, 1H), 2.31 (s, 8H), 0.82 (dd, J = 7.0, 1.8 Hz, 2H), 0.61 (dd, J = 3.8, 2.0 Hz, 2H).

C148 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4; HCl salt; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.51-7.36 (m, 3H), 5.68 (s, 1H), 3.77 (s, 2H), 3.37-3.33 (m, 2H), 2.93-2.84 (m, 1H), 2.47 (s, 3H), 2.07-1.95 (m, 4H), 1.93-1.72 (m, 4H), 1.34-1.19 (m, 1H), 0.88- 0.78 (m, 2H), 0.69-0.59 (m, 4H), 0.45-0.37 (m, 2H).

C149 [C₂₆H₂₈N₆O₂ + H]⁺ 457.2 457.4; TFA salt; 100% at 254 nm (400 MHz, CD₃OD) δ ppm 8.93 (d, J = 7.8 Hz, 2H), 8.57-8.50 (m, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 2H), 6.53 (s, 1H), 3.41 (d, J = 7.0 Hz, 2H), 2.90-2.83 (m, 1H), 2.46 (s, 3H), 2.18-2.08 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H), 0.85-0.77 (m, 2H), 0.66- 0.59 (m, 2H).

C150 [C₂₈H₃₀N₆O₂ + H]⁺ 483.2 483.2; TFA salt; 100% at 254 nm (400 MHz, CD₃OD) δ ppm 8.88 (d, J = 6.0 Hz, 2H), 8.71 (d, J = 6.0 Hz, 2H), 8.56 (s, 1H), 8.12- 8.04 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 6.94 (s,. 1H), 4.02-3.94 (m, 2H), 3.53 (d, J = 7.3 Hz, 2H), 3.44 (t, J = 11.5 Hz, 2H), 2.92-2.82 (m, 1H), 2.49 (s, 3H), 2.16-2.04 (m, 1H), 1.80 (d, J = 13.1 Hz, 2H), 1.53- 1.38 (m, 2H), 0.87-0.79 (m, 2H), 0.67-0.60 (m, 2H).

C151 [C₂₇H₃₁N₇O₂ + H]⁺ 486.3 486.2; free base; 100% at 254 nm (400 MHz, CD₃OD) δ ppm 8.47 (s, 1H), 8.05 (s, 1H), 7.96-7.91 (m, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.52 (s, 1H), 4.38 (s, 3H), 4.02-3.92 (m, 2H), 3.50- 3.39 (m, 4H), 2.90-2.82 (m, 1H), 2.46 (s, 3H), 2.11-1.99 (m, 1H), 1.82-1.73 (m, 2H), 1.50-1.36 (m, 2H), 0.86-0.77 (m, 2H), 0.67-0.59 (m, 2H).

C152 [C₂₆H₂₆N₆O₂ + H]⁺ 455.2 455.2; HCl salt; 95.9% at 254 nm (400 MHz, CD₃OD) δ ppm 9.10 (s, 1H), 8.82 (d, J = 6.0 Hz, 1H), 8.73-8.66 (m, 1H), 8.41 (s, 1H), 8.24-8.15 (m, 1H), 7.69 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H), 3.39 (d, J = 7.0 Hz, 2H), 2.89-2.78 (m, 1H), 2.29 (s, 3H), 1.37-1.23 (m, 1H), 0.86-0.75 (m, 2H), 0.70-0.56 (m, 4H), 0.45-0.38 (m, 2H).

C153 [C₂₆H₃₂N₆O₂ + H]⁺ 461.3 461.3; TFA salt; 96.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.70-7.60 (m, 1H), 7.59-7.49 (m, 1H), 7.42-7.36 (m, 1H), 5.59-5.51 (m, 1H), 4.11-3.94 (m, 3H), 3.61 (t, J = 10.8 Hz, 2H), 3.42-3.34 (m, 2H), 2.91-2.83 (m, 1H), 2.46 (s, 3H), 2.12-2.03 (m, 2H), 1.70-1.56 (m, 2H), 1.31-1.21 (m, 1H), 0.87-0.79 (m, 2H), 0.69- 0.59 (m, 4H), 0.43-0.36 (m, 2H).

C154 [C₃₀H₃₀N₆O + H]⁺ 491.2 491.2; TFA salt; 99.3% at 254 nm (400 MHz, CD₃OD) δ ppm 9.38 (d, J = 9.5 Hz, 1H), 9.09-9.02 (m, 1H), 8.55 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.12-7.99 (m, 3H), 7.96-7.89 (m, 1H), 7.84-7.76 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 3.39 (d, J = 7.3 Hz, 3H), 2.88-2.79 (m, 1H), 2.38 (s, 3H), 2.19-2.06 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H), 0.84-0.74 (m, 2H), 0.64-0.54 (m, 2H).

C155 [C₂₉H₂₈N₆O + H]⁺ 477.2 477.2; TFA salt; 96.2% at 254 nm (400 MHz, CD₃OD) δ ppm 9.67 (d, J = 8.8 Hz, 1H), 9.22-9.18 (m, 1H), 8.61 (s, 1H), 8.34-8.29 (m, 1H), 8.26-8.19 (m, 2H), 8.18-8.13 (m, 2H), 8.04- 7.97 (m, 1H), 7.78 (d, J = 8.5 Hz, 2H), 6.63 (s, 1H), 3.41 (d, J = 7.0 Hz, 2H), 2.87-2.79 (m, 1H), 2.19- 2.07 (m, 1H), 1.07 (d, J = 6.5 Hz, 6H), 0.84-0.76 (m, 2H), 0.66-0.59 (m, 2H).

C156 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3 491.2; HCl salt; 96.2% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.49-7.38 (m, 3H), 5.63 (s, 1H), 4.16-4.07 (m, 1H), 4.04-3.92 (m, 3H), 3.67-3.56 (m, 4H), 2.92-2.83 (m, 1H), 2.47 (s, 5H), 2.31-2.16 (m, 1H), 2.11-2.00 (m, 2H), 1.80-1.57 (m, 4H), 0.86-0.78 (m, 2H), 0.66-0.59 (m, 2H).

C157 [C₂₇H₃₆N₆O₂ + H]⁺ 477.3 477.3; HCl salt; 100% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.53-7.33 (m, 3H), 5.78-5.50 (m, 1H), 3.98 (s, 2H), 3.48-3.33 (m, 2H), 2.93-2.82 (m, 1H), 2.47 (s, 3H), 2.20-2.03 (m, 1H), 1.74 (br, s, 6H), 1.62-1.39 (m, 2H), 1.05 (d, J = 5.5 Hz, 6H), 0.82 (d, J = 6.3 Hz, 2H), 0.63 (d, J = 2.3 Hz, 2H).

C158 [C₂₆H₃₆N₆O₂ + H]⁺ 465.3 465.4; HCl salt; 100% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.51-7.38 (m, 3H), 5.67 (br, s, 1H), 3.93-3.57 (m, 3H), 2.91- 2.83 (m, 1H), 2.47 (s, 3H), 2.16-1.99 (m, 2H), 1.12-1.00 (m, 12H), 0.86-0.78 (m, 2H), 0.66-0.56 (m, 2H).

C159 [C₂₇H₂₈N₆O₃ + H]⁺ 485.2 485.2; HCl salt; 98.6% at 254 nm (400 MHz, CD₃OD) δ ppm 9.14 (s, 1H), 8.85 (d, J = 5.5 Hz, 1H), 8.79-8.72 (m, 1H), 8.40 (s, 1H), 8.30-8.21 (m, 1H), 7.68 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 4.17-4.06 (m, 1H), 3.54 (d, J = 6.5 Hz, 2H), 2.88- 2.78 (m, 1H), 2.53-2.43 (m, 2H), 2.29 (s, 4H), 1.81-1.68 (m, 2H), 0.84-0.77 (m, 2H), 0.62-0.56 (m, 2H).

C160 [C₂₆H₂₉N₇O + H]⁺ 456.2 457.2; HCl salt; 98.8% al 254 nm (400 MHz, CD₃OD) δ ppm 9.70 (s, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.42-8.34 (m, 1H), 8.31 (s, 1H), 8.02-7.93 (m, 1H), 7.88-7.77 (m, 2H), 7.43 (d, J = 8.3 Hz, 1H), 3.24 (d, J = 6.8 Hz, 2H), 2.94-2.84 (m, 1H), 2.47 (s, 3H), 2.17-2.02 (m, 1H), 1.06 (d, J = 6.8 Hz, 6H), 0.90-0.80 (m, 2H), 0.70-0.60 (m, 2H).

C161 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3 505.3; HCl salt; 95.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.24 (s, 1H), 7.52-7.36 (m, 3H), 5.52 (br, s, 1H), 4.31 (br, s, 1H), 4.02-3.93 (m, 2H), 3.89-3.81 (m, 1H), 3.80-3.65 (m, 3H), 3.53-3.38 (m, 4H), 2.91-2.82 (m, 1H), 2.45 (s, 3H), 2.33-2.20 (m, 1H), 2.18-2.02 (m, 3H), 1.97-1.88 (m, 1H), 1.79-1.69 (m, 2H), 1.50-1.37 (m, 2H), 0.87-0.78 (m, 2H), 0.66-0.57 (m, 2H).

C162 [C₂₉H₃₆N₆O₃ + H]⁺ 517.3 517.3; free base; 96.2% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.94 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.15 (s, 1H), 4.14-4.03 (m, 4H), 4.01-3.92 (m, 2H), 3.50-3.39 (m, 3H), 3.27 (s, 2H), 2.89-2.80 (m, 1H), 2.65-2.54 (m, 2H), 2.44 (s, 3H), 2.22-2.11 (m, 2H), 2.05-1.93 (m, 1H), 1.80-1.70 (m, 2H), 1.47- 1.32 (m, 2H), 0.85-0.76 (m, 2H), 0.66-0.57 (m, 2H).

C163 [C₃₁H₄₂N₆O₃ + H]⁺ 547.3; 547.3 HCl salt; 97.9% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.55-7.32 (m, 3H), 5.68 (br, s, 1H), 3.97 (d, J = 11.5 Hz, 2H), 3.90-3.51 (m, 3H), 3.42 (t, J = 11.2 Hz, 4H), 2.93- 2.78 (m, 1H), 2.46 (s, 3H), 2.15-1.97 (m, 1 H), 1.93-1.63 (m, 8H), 1.50-1.07 (m, 7H), 0.86-0.77 (m, 2H), 0.69-0.55 (m, 2 H).

C164 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; HCl salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.44-4.29 (m, 1H), 3.97 (dd, J = 11.3, 3.8 Hz, 2H), 3.86-3.77 (m, 1H), 3.76-3.58 (m, 2H), 3.53- 3.38 (m, 3H), 3.28 (d, J = 7.0 Hz, 2H), 2.90-2.79 (m, 1H), 2.44 (s, 3H), 2.21-1.91 (m, 5H), 1.76 (d, J = 12.5 Hz, 2H), 1.49-1.32 (m, 2H), 0.81 (dd, J = 7.0, 1.8 Hz, 2H), 0.62 (dd, J = 4.0, 2.0 Hz, 2H).

C165 [C₃₀H₄₀N₆O₃ + H]⁺ 533.3; 534.3; HCl salt; 96.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1 H), 7.58-7.24 (m, 3H), 5.68 (br, s, 1H), 4.10-3.60 (m, 5H), 3.45- 3.38 (m, 4H), 2.87 (br, s, 1 H), 2.46 (s, 3H), 2.31- 1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.80-1.54 (m, 6H), 1.50-1.25 (m, 4H), 0.82 (d, J = 6.0 Hz, 2H), 0.62 (br, s, 2H).

C166 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; HCl salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 8.06-7.82 (m, 2 H), 7.30 (d, J = 7.8 Hz, 1H), 5.25 (s, 1H), 3.97 (d, J = 7.5 Hz, 2H), 3.84-3.51 (m, 5H), 3.43 (t, J = 11.4 Hz, 2H), 3.26 (d, J = 6.5 Hz, 2H), 2.94- 2.77 (m, 1H), 2.62-2.50 (m, 1H), 2.44 (s, 3H), 2.23-2.09 (m, 1H), 2.08-1.94 (m, 1H), 1.89-1.81 (m, 1H), 1.76 (d, J = 12.5 Hz, 2H), 1.48-1.31 (m, 2H), 0.88-0.73 (m, 2H), 0.68-0.52 (m, 2H).

C167 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; HCl salt; 97.7% at 254 nm (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 8.06-7.82 (m, 2 H), 7.30 (d, J = 7.8 Hz, 1H), 5.25 (s, 1H), 3.97 (d, J = 7.5 Hz, 2H), 3.84-3.51 (m, 5H), 3.43 (t, J = 11.4 Hz, 2H), 3.26 (d, J = 6.5 Hz, 2H), 2.94- 2.77 (m, 1H), 2.62-2.50 (m, 1H), 2.44 (s, 3H), 2.23-2.09 (m, 1H), 2.08-1.94 (m, 1H), 1.89-1.81 (m, 1H), 1.76 (d, J = 12.5 Hz, 2H), 1.48-1.31 (m, 2H), 0.88-0.73 (m, 2H), 0.68-0.52 (m, 2H).

C168 [C₂₉H₃₉N₇O₂ + H]⁺ 518.3; 518.4; di-HCl salt; 99.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.65-7.20 (m, 3H), 6.24-5.48 (m, 2H), 4.46-4.28 (m, 1H), 4.19-3.96 (m, 2H), 3.94-3.62 (m, 1H), 3.59-3.38 (m, 4H), 3.25-3.08 (m, 1H), 2.87 (br, s, 1H), 2.47 (s, 3H), 2.19 (br, s, 4H), 2.00-1.45 (m, 7H), 0.97- 0.74 (m, 2H), 0.71-0.50 (m, 2H).

C169 [C₂₈H₃₆FN₇O + H]⁺ 506.3; 506.4; di-HCl salt; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.22 (br, s, 1H), 7.57- 7.33 (m, 3H), 5.76 (br, s, 1H), 4.34-4.12 (m, 1H), 4.05-3.79 (m, 2H), 3.53-3.37 (m, 2H), 3.28-3.15 (m, 2H), 2.94-2.81 (m, 1H), 2.47 (s, 3H), 2.35-1.98 (m, 6H), 1.91-1.57 (m, 6H), 0.82 (m, J = 6.3 Hz, 2H), 0.68-0.54 (m, 2H).

C170 [C₂₉H₃₈FN₇O + H]⁺ 520.3; 520.4; di-HCl salt; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.23 (s, 1H), 7.53-7.33 (m, 3H), 5.75 (br, s, 1H), 4.34-4.11 (m, 1H), 4.03- 3.80 (m, 2H), 3.64-3.44 (m, 3H), 3.00-2.79 (m, 4H), 2.47 (s, 3H), 2.39-2.06 (m, 6H), 1.92-1.55 (m, 7H), 0.88-0.76 (m, 2H), 0.62 (m, J = 1.8 Hz, 2H).

C171 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4; HCl salt; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 8.08 (s, 1H), 7.89 (dd, J = 8.2, 1.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.30 (s, 1H), 4.42-4.25 (m, 1H), 4.15- 4.02 (m, 1H), 2.86-2.83 (m, J = 7.4 Hz, 1H), 2.51- 2.45 (m, 2H), 2.44 (s, 3H), 2.22-2.04 (m, 3H), 1.83-1.51 (m, 8H), 0.87-0.76 (m, 2H), 0.68- 0.55 (m, 2H).

C172 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4; HCl salt; 97.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.55-7.29 (m, 3H), 5.54 (br, s, 1H), 4.50-4.37 (m, 1H), 4.26- 4.07 (m, 1H), 3.62 (d, J = 6.8 Hz, 2H), 2.92-2.83 (m, 1H), 2.75-2.61 (m, 1H), 2.46 (s, 3H), 2.31-2.02 (m, 6H), 1.92-1.56 (m, 6H), 0.91-0.75 (m, 2H), 0.71-0.52 (m, 2H).

C173 [C₂₈H₃₅FN₆O₂ + H]⁺ 507.3; 507.4; HCl salt; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.33 (s, 1H), 7.80-7.52 (m, 2H), 7.39 (br, s, 1H), 5.49 (br, s, 1H), 4.10-3.80 (m, 2H), 3.53-3.38 (m, 3H), 3.28-3.05 (m, 2H), 2.88 (br, s, 1H), 2.45 (s, 3H), 2.33-1.57 (m, 12H), 0.92-0.75 (m, 2H), 0.70-0.50 (m, 2H).

C174 [C₂₉H₃₇FN₆O₂ + H]⁺ 521.3; 521.5; HCl salt; 98.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.33 (s, 1H), 7.86 (br, s, 1H), 7.76 (d, J = 5.8 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 5.86 (br, s, 1H), 5.50 (br, s, 1H), 3.81 (d, J = 19.8 Hz, 2H), 3.64-3.38 (m, 2H), 3.25-3.13 (m, 2H), 2.99-2.72 (m, 5H), 2.44 (s, 3H), 2.34-2.00 (m, 6H), 1.98-1.56 (m, 6H), 0.92-0.72 (m, 2H), 0.67- 0.44 (m, 2H).

C175 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 TFA salt; 96.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.54-7.38 (m, 3H), 5.57 (s, 1H), 4.00-3.86 (m, 3H), 3.81-3.55 (m, 4H), 3.44 (d, J = 7.0 Hz, 2H), 2.93-2.82 (m, 1H), 2.48 (s, 3H), 2.15-1.49 (m, 13H), 0.91-0.78 (m, 2H), 0.69-0.52 (m, 2H).

C176 [C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.2 TFA salt; 98.6% at 254 nm (400 MHz, CD₃OD) δ ppm 8.91 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 5.3 Hz, 1H), 8.44-8.32 (m, 2H), 8.06-7.91 (m, 1H), 7.70 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.98 (s, 1H), 4.01-3.84 (m, 1H), 3.38 (d, J = 7.0 Hz, 2H), 2.88- 2.79 (m, 1H), 2.28 (s, 3H), 1.96-1.51 (m, 9H), 0.84-0.76 (m, 2H), 0.64-0.58 (m, 2H).

C177 [C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.2 HCl salt; 99.8% at 254 nm (400 MHz, CD₃OD) δ ppm 9.05-8.87 (m, 1H), 8.74 (d, J = 5.5 Hz, 1H), 8.42-8.51 (m, 1H), 8.39 (s, 1H), 8.09-8.00 (m, 1H), 7.70 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.00 (s, 1H), 3.62-3.48 (m, 1H), 3.44-3.33 (m, 2H), 2.87- 2.79 (m, 1H), 2.29 (s, 3H), 2.22-2.10 (m, 1H), 2.09-1.49 (m, 4H), 1.40-1.05 (m, 4H), 0.93-0.75 (m,2H), 0.67-0.53 (m, 2H).

C178 [C₃₀H₃₄FN7O₂ + H]⁺ 544.3; 544.3 di-TFA salt; 96.5% at 254 nm (4400 MHz, CD₃OD) δ ppm 8.38 (s, 1H), 7.85 (s, 1H), 7.64 (dd, J = 7.80, 1.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.18-6.97 (m, 3H), 5.92 (s, 1H), 3.62 (t, J = 6.3 Hz, 2H), 2.92 (s, 3H), 2.89 (t, J = 6.0 Hz, 2H), 2.86-2.79 (m, 1H), 2.28 (s, 3H), 0.84-0.78 (m, 2H), 0.64-0.57 (m, 2H); 8H peaks due to the piperazine are either very broad or obscured by the peaks due the solvent and H₂O at 3.33 ppm and/or 4.88 pm.

C179 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 TFA salt; 99.4% at 254 nm (400 MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.64-7.47 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H), 5.58 (s, 1H), 4.10-3.92 (m, 4H), 3.70-3.56 (m, 2H), 3.43 (d, J = 6.0 Hz, 2H), 2.95-2.83 (m, 1H), 2.47 (s, 3H), 2.13- 2.04 (m, 2H), 1.93-1.74 (m., 3H), 1.72-1.48 (m, 8H), 0.91-0.79 (m, 2H), 0.69-0.57 (m, 2H).

C180 [C₃₀H₃₃FN₆O₂ + H]⁺ 529.3; 529.3 TFA salt; 97.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.39 (s, 1H), 7.83 (s, 1H), 7.67-7.58 (m, 1H), 7.56-7.41 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16-7.01 (m, 3H), 6.01 (s, 1H), 3.90 (t, J = 6.3 Hz, 2H), 3.74-3.57 (m, 2H), 3.48 (t J = 6.3 Hz, 2H), 3.11-2.99 (m, 2H), 2.90-2.75 (m, 1H), 2.27 (s, 3H), 2.03-1.92 (m, 2H), 1.92-1.73 (m, 3H), 1.66-1.48 (m, 1H), 0.81 (s, 2H), 0.68-0.52 (m, 2H).

C181 [C₂₉H₃₁FN₆O₃ + H]⁺ 530.2; 530.3 TFA salt; 97.9% at 254 nm (400 MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.79 (s, 1H), 7.59 (dd, J = 8.0, 1.8 Hz, 1H), 7.30-7.14 (m, 5H), 5.98 (s, 1H), 4.17-3.98 (br. s., 2H), 3.91 (t, J = 6.3 Hz, 2H), 3.98-3.74 (br.s. 2H), 3.55 (t, J = 6.2 Hz, 3H), 3.74-3.45 (br.s, 2H) 3.40-3.15 (br.s. 2H), 2.87-2.80 (m, 1H), 2.26 (s, 3H), 0.85-0.77 (m, 2H), 0.66-0.54 (m, 2H).

C182 [C₃₀H₃₃FN₆O₃ + H]⁺ 545.3 545.3; TFA salt; 98.5% at 254 nm (400 MHz, CD₃OD) δ ppm 8.36 (s, 1H), 7.82 (s, 1H), 7.60 (d, J = 9.3 Hz, 1H), 7.53-7.41 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16-7.02 (m, 3H), 5.98 (s, 1H), 4.18-4.05 (m, 0.5H), 3.89 (br. s., 2.5H), 3.79-3.65 (m, 1H), 3.49 (br. s., 3H), 3.45-3.34 (m, 1H), 3.21-3.07 (m, 1H), 2.88-2.77 (m, 1H), 2.27 (s, 3H), 2.23-1.67 (m, 4H), 0.85-0.77 (m, 2H), 0.66- 0.55 (m, 2H).

C183 [C₃₀H₄₁N₇O₃ + H]⁺ 548.3; 548.4 TFA salt; 98.3% at 254 nm (400 MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.60-7.35 (m, 3H), 5.79 (s, 1H), 4.14-3.93 (m, 4H), 3.92-3.63 (m, 2H), 3.60-3.49 (m, 3H), 3.48-3.37 (m, 1H), 3.23-3.07 (m, 1H), 2.87 (s, 1H), 2.48 (s, 3H), 2.25- 1.39 (m, 12H), 0.88-0.79 (m, 2H), 0.68-0.61 (m, 2H).

C184 [C₂₉H₃₇F₂N₇O + H]⁺ 538.3; 538.4 TFA salt; 97.8% at 254 nm (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H), 7.52-7.37 (m, 3H), 5.69 (s, 1H), 4.29-4.20 (m, 1H), 4.10-3.99 (m, 2H), 3.72-3.46 (m, 6H), 2.94-2.80 (m, 1H), 2.46 (s, 3H), 2.44-2.33 (m, 4H), 2.24-2.06 (m, 2H), 1.91-1.58 (m, 6H), 0.89-0.77 (m, 2H), 0.69-0.51 (m, 2H).

C185 [C₂₈H₃₂F₂N₈O₂ + H]⁺ 551.3: 551.4 HCl salt; 98.1% at 254 nm (400 MHz, CD₃OD) δ ppm 8.42 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.02 (s, 1H), 4.00- 3.91 (m, 5H), 3.85 (br. s., 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.42 (br. s., 2H), 2.93-2.76 (m, 1H), 2.52-2.32 (m, 7H), 0.86-0.75 (m, 2H), 0.69-0.55 (m, 2H).

C186 [C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.4 TFA salt; 98.2% at 254 nm (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.48-7.36 (m, 3H), 5.52 (s, 1H), 4.23-4.10 (m, 1H), 3.65-3.57 (m, 2H), 2.93-2.75 (m, 2H), 2.46 (s, 3H), 2.31-2.21 (m, 2H), 2.20-2.11 (m, 3H), 2.06-1.89 (m, 2H), 1.89-1.50 (m, 6H), 1.37 (s, .3H), 0.87-0.79 (m, 2H), 0.68-0.56 (m, 2H).

C187 [C₂₇H₂₉FN₆O₂ + H]+ 489.2; 489.2 TFA salt; 94.0% at 254 nm (400 MHz, CD₃OD) δ ppm 8.39 (s, 1H), 7.83 (d, J = 0.5 Hz, 1H), 7.70-7.59 (m, 1H), 7.55-7.45 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.15-6.98 (m, 3H), 6.05 (s, 1H), 3.90 (t, J = 6.3 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 3.02 (s, 6H), 2.84 (s, 1H), 2.27 (s, 3H), 0.85-0.75 (m, 2H), 0.66-0.57 (m, 2H).

Example B: TTK Inhibition Assay

Active TTK was purchased from Invitrogen as an amino terminal GST fusion of full length human TTK. Amino terminal 6 histidine, sumo tagged human TTK (residues 1-275) was expressed in E. coli, and purified to >95% homogeneity by Ni²⁺ agarose, gel filtration, and ion exchange chromatography.

TTK activity was measured using an indirect ELISA detection system. GST-TTK (0.68 nM) was incubated in the presence of either 16 μM ATP (Sigma cat# A7699) or 100 μM ATP, 50 mM Hepes pH 7.2, 1 mM EGTA, 10 mM MgCl₂, and 0.1% Pluronic in a 96 well microtitre plate pre-coated with amino terminal 6 histidine, sumo tagged TTK (amino acid residues 1-275).

The reaction was allowed to proceed for 30 minutes, followed by 5 washes of the plate with Wash Buffer (phosphate buffered saline supplemented with 0.2% Tween 20), and incubation for 30 minutes with a 1:3000 dilution of primary antibody (Cell Signaling cat#9381). The plate was washed 5 times with Wash Buffer, incubated for 30 minutes in the presence of secondary antibody coupled to horse radish peroxidase (BioRad cat#1721019, 1:3000 concentration), washed an additional 5 times with Wash Buffer, and incubated in the presence of TMB substrate (Sigma cat# T0440). The colourimetric reaction was allowed to continue for 5 minutes, followed by addition of stop solution (0.5 N sulphuric acid), and quantified by detection at 450 nm with either a monochromatic or filter based plate reader (Molecular Devices M5 or Beckman DTX880, respectively).

Compound inhibition was determined at either a fixed concentration (10 μM) or at a variable inhibitor concentration (typically 0.5 μM to 0.001 μM in a 10 point dose response titration). Compounds were pre-incubated in the presence of enzyme for 5 minutes prior to addition of ATP and the activity remaining quantified using the above described activity assay. The % Inhibition of a compound was determined using the following formula; % Inhibition=100×(1−(experimental value−background value)/(high activity control−background value)). The IC₅₀ value was determined using a non-linear 4 point logistic curve fit (XLfit4, IDBS) with the formula; (A+(B/(1+((x/C)̂D)))), where A=background value, B=range, C=inflection point, D=curve fit parameter.

In Table 1 and 2 below, IC₅₀ value ranges for compound examples are given using 16 μM ATP (Sigma cat# A7699). The IC₅₀ ranges are indicated as “A,” “B,” and “C,” for values less than or equal to 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM; and those greater than 0.5 μM, respectively. IC₅₀ ranges denoted with an asterisk indicated that 16 μM ATP (Sigma cat# A7699) was used in the assay.

In Table 3 below, IC₅₀ value ranges for exemplary compounds are given using 100 μM ATP. The IC₅₀ ranges are indicated as “A,” “B,” and “C,” for values less than or equal to 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM; and those greater than 0.5 μM, respectively. IC₅₀ ranges denoted with an asterisk indicated that 16 μM ATP (Sigma cat# A7699) was used in the assay.

Example C: Cancer Cell Line Data on Exemplary Compounds of the Invention

Breast cancer cells (MDA-MB-231 and MDA-MB-468), colon cancer cells (HCT116) and ovarian cancer cells (PA-1 and OVCAR-3) were seeded (1000 to 4000 in 80 μl per well depending on the cell growth rate) into 96 well plates 24 hours before compound overlay. Compounds were prepared as 10 mM stock solutions in 100% DMSO which were diluted with DMEM (Dulbecco's Modified Eagle's Medium) cell growth Medium (Invitrogen, Burlington, ON, Canada) containing 10% FBS (Fetal Bovine Serum) to concentrations ranging from 50 nM to 250 μM. Aliquots (20 μl) from each concentration were overlaid to 80 μl of the pre-seeded cells in the 96 well plates to make final concentrations of 10 nM to 50 μM. The cells were cultured for 5 days before the Sulforhodamine B assay (SRB) was performed to determine the compound's cell growth inhibition activity.

Sulforhodamine B (purchased from Sigma, Oakville, ON, Canada) is a water-soluble dye that binds to the basic amino acids of the cellular proteins. Thus, colorimetric measurement of the bound dye provides an estimate of the total protein mass that is related to the cell number. the cells are fixed in situ by gently aspirating off the culture media and adding 50 μl ice cold 10% Trichloroacetic Acid (TCA) per well and incubate at 4° C. for 30-60 min, The plates are washed with H₂O five times and allowed to air dry for 5 min. Addition of 50 μl 0.4% (w/v) SRB solution in 1% (v/v) acetic acid to each well and incubation for 30 min at RT completes the staining reaction. Following staining, plates are washed four times with 1% acetic acid to remove unbound dye and then allowed to air dry for 5 min. The stain is solubilized with 100 μl of 10 mM Tris pH 10.5 per well. Absorbance is read at 570 nm.

The percentage (%) of relative growth inhibition was calculated by comparing to DMSO treated only cells (100%). GI₅₀'s were determined for compounds with cytotoxic activity. The GI₅₀ was calculated using GraphPad PRISM software (GraphPad Software, Inc., San Diego, Calif., USA). GI₅₀ (growth inhibition) is the compound concentration that causes 50% inhibition of cell growth.

In Table 1 below, GI₅₀ value ranges for compound examples against breast cancer cell lines (MDA-MB-468), colon cancer cell lines (HCT116) and ovarian cancer cell lines (PA-1) are given. The example compounds demonstrated varying growth inhibition/cell killing activity against cells of breast cancer, colon cancer, and ovarian cancer. The GI₅₀ ranges are indicated as “A,” “B,” and “C,” for values less than or equal to 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM; and those greater than 0.5 μM, respectively.

In Table 2 below, GI₅₀ value ranges for compound examples against breast cancer cell lines (MDA-MB-231), colon cancer cell lines (HCT116) and ovarian cancer cell lines (PA-1) are given. The example compounds demonstrated varying growth inhibition/cell killing activity against cells of breast cancer, colon cancer, and ovarian cancer. The GI₅₀ ranges are indicated as “A,” “B,” and “C,” for values less than or equal to 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM; and those greater than 0.5 μM, respectively.

In Table 3 below, GI₅₀ value ranges for compound examples against breast cancer cell lines (MDA-MB-468), colon cancer cell lines (HCT116) and ovarian cancer cell lines (OVCAR-3) are given. The example compounds demonstrated varying growth inhibition/cell killing activity against cells of breast cancer, colon cancer, and ovarian cancer. The GI₅₀ ranges are indicated as “A,” “B,” and “C,” for values less than or equal to 0.1 μM; those greater than 0.1 τM and less than or equal to 0.5 μM; and those greater than 0.5 μM, respectively.

Example D: Colon and Ovarian Cancer Tumor-Initiating Cell Data of Exemplary Compounds

Materials and Methods:

Non-tissue or tissue cultured treated T-75 flask and 96-well plates were purchased from VWR. Vitamin B-27 supplement, MEM NEAA (minimum essential medium non essential amino acids), sodium pyruvate, L-glutamine, N2 supplement, penicillin-streptomycin and fungizone/amphotericin B were obtained from Invitrogen. Lipid mixture, heparin and EGF were purchased from Sigma; bFGF from BD Biosciences. Tumor Initiating Cells (TICs) from colon were routinely maintained using non-tissue cultured treated T-75 flasks in DMEM:F12 medium containing 0.2×B-27 supplement, 4 ug/ml heparin, 1×MEM NEAA, 1× sodium pyruvate, 1 mM glutamine, 10 pg/ul bFGF, 20 pg/ul EGF, 1×N2 supplement, lipid mixture, penicillin-streptomycin and fungizone/amphotericin B. Ovarian TICs were routinely maintained using tissue cultured treated T-75 flasks in DMEM:F12 medium containing 1×B-27 supplement, 4 ug/ml heparin, 20 pg/ul bFGF, 20 pg/ul EGF and penicillin-streptomycin.

Assay Protocol:

Compounds described herein were dissolved in DMSO and further diluted in cell culture medium for GI₅₀ determination. Colon TICs were trypsinized and seeded into non-tissue cultured treated 96-well plates with 4,000 cells/well. After 24 h, compound was added into the cell culture at different concentrations, and the final concentration of DMSO was adjusted to 0.1%. Cells were then cultured at 37° C. for 9 days. Ovarian TICs were trypsinized and seeded into tissue cultured treated 96-well plates with 1,000 cells/well. After 24 h, compound was added into the cell culture at different concentrations, and the final concentration of DMSO was adjusted to 0.1%. Cells were then cultured at 37° C. for 6 days. Cell viability was assessed by Alamar Blue assay: 10 ul of Alamar Blue was added into each well. After 4 hours incubation at 37° C., fluorescence was recorded at excitation 544 and emission 590. GI₅₀ (Growth inhibition) was calculated using GraphPad Prism 4.0 software. Cell growth inhibition data for compounds described herein is tabulated below.

In Table 1 below, GI₅₀ value ranges for compound examples against TICs (Colon 12 and Ovarian 2393A) are given. The GI₅₀ ranges are indicated as “A,” “B,” and “C,” for values less than or equal to 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM; and those greater than 0.5 μM, respectively.

TABLE 1 In vitro activity of Compound Examples Tumor Cancer Cell Line Initiating Cell TTK GI₅₀ Range GI₅₀ Range Example IC₅₀ MDA- Ovarian # Range HCT116 MB-468 PA-1 2393A Colon 12 A1 B* ND ND ND ND ND A2 A* B B A B A A3 A* A A A B A A4 A* B B B B A A5 A* B C B C B A6 A* B C A B B A7 A* C C B C C A8 C* C C C ND ND A9 C* ND ND ND ND ND A10 A* B C B ND ND A11 A* B C B ND ND A12 C* C C C ND ND A13 A* C C B ND ND A14 A* B C B C C A15 A* B C B B B ND—not determined IC₅₀ ranges denoted with an asterisk indicated that 16 μM ATP (Sigma cat# A7699) was used in the assay.

TABLE 2 In vitro activity of Compound Examples Tumor Cancer Cell Line Initiating Cell TTK GI₅₀ Range GI₅₀ Range Example IC₅₀ MDA- Ovarian # Range HCT116 MB-231 PA-1 2393A Colon 12 B2 A* C C B C B B3 A* A B A B B B1 A* A A A A A B4 A* ND ND ND ND ND B5 A* A A A A A B14 A* A A A A A B15 C* ND ND ND ND ND B6 A* B B A B B B16 A* A A A A A B18 A* A B A A A B7 A* A A A A A B8 A* B B A B B B19 A* B B A B B B20 A* A A A A A B17 A* A A A A A B9 A* A A A A A B10 A* B C B ND ND B11 A* B B B ND ND B12 A* A A A A A B13 A* A A A B A B29 A* B C B C B B21 A* A B A ND ND B22 A* A A A ND ND B25 A* A A A ND ND B23 A* B B B ND ND B26 A* A B A ND ND B24 A* A A A ND ND B31 A* A A A ND ND B30 A* ND ND ND ND ND B27 A* ND ND ND ND ND B28 A* ND ND ND ND ND B32 A* ND ND ND ND ND B33 A* ND ND ND ND ND ND—not determined IC₅₀ ranges denoted with an asterisk indicated that 16 μM ATP (Sigma cat# A7699) was used in the assay.

TABLE 3 In vitro activity of Compound Examples Tumor Initiating Cell GI₅₀ Cancer Cell Line GI₅₀ Range Range Exam- TTK IC₅₀ MDA- OVCAR- Ovarian Colon ple # Range MB-468 HCT116 3 2393A 12 C1 A* ND ND ND ND ND C2 B* ND ND ND ND ND C3 C* ND ND ND ND ND C4 B* ND ND ND ND ND C5 C* ND ND ND ND ND C6 A* ND ND ND ND ND C7 A* C C C B B C8 A* B B B ND ND C9 A* C C B ND ND C10 A* C C C C C C11 A* C C C B B C12 A* ND ND ND ND ND C13 A* B B C ND ND C14 A* A A A A A C15 A* ND ND ND ND ND C16 A* ND ND ND ND ND C17 C* ND ND ND ND ND C18 C* ND ND ND ND ND C19 A* B C C ND ND C20 A* B A B B A C21 A* A A A A A C22 A* B B B ND ND C23 A* C B C ND ND C24 A* A A A A A C25 A* B A B B A C26 A* B A B A A C27 A* B A B ND ND C28 A A A A A A C29 A ND ND ND ND ND C30 A C C C ND ND C31 A A A A A A C32 A A A A A A C33 A A A A ND ND C34 A A A A ND ND C35 A A A A ND ND C36 A A A A ND ND C37 A A A A A A C38 A A A A A A C39 A A A A A A C40 A A A B B A C41 A A A A B A C42 A A A A A A C43 A A A A ND ND C44 A A A A ND ND C45 A A A A B A C46 A A A B A A C47 A A A A ND ND C48 A B B B B B C49 A B B B ND ND C50 C ND ND ND ND ND C51 A B B B ND ND C52 A B B C ND ND C53 A ND ND ND ND ND C54 A B B B ND ND C55 A B A B ND ND C56 A A A A ND ND C57 A B B B ND ND C58 A B A B ND ND C59 A B B B ND ND C60 A ND ND ND ND ND C61 A A A A ND ND C62 A B B B ND ND C63 A ND ND ND ND ND C64 A ND ND ND ND ND C65 A ND ND ND ND ND C66 A B B B ND ND C67 A ND ND ND ND ND C68 A B C B ND ND C69 B ND ND ND ND ND C70 A ND ND ND ND ND C71 A B B C ND ND C72 A A A B ND ND C73 A ND ND ND ND ND C74 A B B C ND ND C75 A ND ND ND ND ND C76 A ND ND ND ND ND C77 A B B B ND ND C78 A B B B ND ND C79 A C C C ND ND C80 A ND ND ND ND ND C81 A ND ND ND ND ND C82 A B B B ND ND C83 A B A B ND ND C84 A ND ND ND ND ND C85 A B B B ND ND C86 B ND ND ND ND ND C87 A B B C ND ND C88 A B C C ND ND C89 A C B C ND ND C90 A B B C ND ND C91 A ND ND ND ND ND C92 A C B C ND ND C93 A ND ND ND ND ND C94 A C C C ND ND C95 A C B C ND ND C96 A C C C ND ND C97 A B A B ND ND C98 A C B C ND ND C99 A C B C ND ND C100 A B B B A A C101 B ND ND ND ND ND C102 A ND ND ND ND ND C103 A B A B ND ND C104 A B A B ND ND C105 A A A A ND ND C106 B ND ND ND ND ND C107 A B B C ND ND C108 A B A A ND ND C109 A B A B ND ND C110 A ND ND ND ND ND C111 A B B B ND ND C112 A ND ND ND ND ND C113 A B B B ND ND C114 A C C C ND ND C115 A ND ND ND ND ND C116 A B A B B B C117 A ND ND ND ND ND C118 A B A B B B C119 A ND ND ND ND ND C120 A B B C C C C121 A B B C ND ND C122 A ND ND ND ND ND C123 A A A B ND ND C124 A B B B ND ND C125 A A A B ND ND C126 A A A A ND ND C127 A B A B ND ND C128 A ND ND ND ND ND C129 A ND ND ND ND ND C130 A B A B A A C131 A B B C ND ND C132 A B C C ND ND C133 A B B B ND ND C134 A B B B ND ND C135 A A A B ND ND C136 A A A B ND ND C137 A ND ND ND ND ND C138 A B A B ND ND C139 A B B B ND ND C140 A ND ND ND ND ND C141 A B A B ND ND C142 B ND ND ND ND ND C143 B C C C ND ND C144 A A A A A A C145 A B B B B B C146 A A A B A A C147 A B B C ND ND C148 A B B C ND ND C149 B ND ND ND ND ND C150 A B B B B B C151 A B A B ND ND C152 A A A A ND ND C153 A B A B ND ND C154 B ND ND ND ND ND C155 C ND ND ND ND ND C156 A B B B ND ND C157 A A A A ND ND C158 A B A B ND ND C159 A A A A ND ND C160 A ND ND ND ND ND C161 A B A B ND ND C162 A ND ND ND ND ND C163 A B A B ND ND C164 A B B C ND ND C165 A B A B B A C166 A ND ND ND ND ND C167 A ND ND ND ND ND C168 A ND ND ND ND ND C169 A C B C ND ND C170 A B B C ND ND C171 A A A B ND ND C172 A A A A ND ND C173 A C B C ND ND C174 A C B C ND ND C175 A A A B B B C176 A A A A A A C177 A B B B A A C178 A A A B ND ND C179 A A A A ND ND C180 A B A B ND ND C181 A B A B ND ND C182 A A A A A A C183 A B C C ND ND C184 A ND ND ND ND ND C185 A ND ND ND ND ND C186 A B A B ND ND C187 A A A B A A ND—not determined IC₅₀ ranges denoted with an asterisk indicated that 16 μM ATP (Sigma cat# A7699) was used in the assay. 

1-34. (canceled)
 35. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is —NR^(a1)R^(b1), —OR^(c1), —SR^(c1), —SOR^(c1), or —SO₂R^(c1); R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl; R³ is —C(═O)NR^(d)R^(e) or —NHC(═O)R⁵; each R⁴ is independently selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl; R^(a1) and R^(b1) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or R^(a1) and R^(b1), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring; R^(a2) and R^(b2) are each independently selected from —H, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or R^(a2) and R^(b2), together with the nitrogen to which they are attached, form an optionally substituted 3-8 membered ring; R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl; R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6 membered monocyclic heteroaryl; R^(d) and R^(e) are each independently selected from —H, optionally substituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclic heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered monocyclic heteroaryl; or R^(d) and R^(e), together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring; and m is 0, 1, 2, or
 3. 36. The compound of claim 35, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: X is NH or O; R⁵ is selected from (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; R¹¹ is (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, —C(═O)NH₂, and —SO₂CH₃; R^(d) and R^(e) are each independently selected from —H, (C₁-C₇)alkyl, (C₃-C₇) cycloalkyl, wherein each of the (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and n is 0, 1, 2, or
 3. 37. (canceled)
 38. The compound of claim 36, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 39. The compound of claim 38, wherein R^(b2) is —H or CH₃.
 40. The compound of claim 39, wherein R^(a2) is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl; wherein each of which is optionally substituted with one or more groups selected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 41. The compound of claim 40, wherein R^(a2) is methyl, ethyl, t-butyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, pyridyl, or phenyl, wherein each of the cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, pyridyl, and phenyl is optionally substituted with one or more groups selected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 42. The compound of claim 38, wherein R^(a2) and R^(b2), together with the nitrogen to which they are attached, form a 3-7 membered monocyclic heterocycloalkyl, optionally substituted with one or more groups selected from halogen, CN, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)(C₁-C₃)alkyl, and 3-7 membered monocyclic heterocycloalkyl.
 43. (canceled)
 44. The compound of claim 36, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 45. The compound of claim 44, wherein R^(c2) is (C₃-C₇)cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₇)cycloalkyl, and —C(═O)H.
 46. The compound of claim 45, wherein R^(c2) is cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, or azetidinyl, wherein each of the cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, and pyridyl is optionally substituted with one or more groups selected from halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, and (C₁-C₃)alkoxy; and the nitrogen in the azetidinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₅)cycloalkyl, or —C(═O)H.
 47. The compound of claim 46, wherein X is NH and R⁴ is selected from hydrogen, halogen, and (C₁-C₃)alkyl.
 48. (canceled)
 49. The compound of claim 36, wherein R¹¹—(CH₂)_(n)—X— is represented by the one of the following structural formulae:


50. The compound of claim 36, wherein R² is represented by the one of the following structural formulae:


51. (canceled)
 52. The compound of claim 50, wherein R⁴ is chlorine or methyl, and is ortho to —C(═O)NR^(d)R^(e).
 53. The compound of claim 36, wherein R¹¹ is ethyl, isopropyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl, wherein each substitutable carbon in the morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl is optionally substituted with —OH, halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen in the piperazinyl is optionally substituted with (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, or —C(═O)H.
 54. The compound of claim 53, wherein R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl, wherein both of which are optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 55. The compound of claim 52, wherein R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl, wherein both of which are optionally substituted with one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 56. The compound of claim 55, wherein R^(d) is cyclopropyl.
 57. A pharmaceutical composition comprising a compound of claim 35 and a pharmaceutically acceptable carrier or diluent.
 58. A method for treating cancer, the method comprising: administering to a subject in need thereof an effective amount of the compound of claim
 35. 59. The method of claim 58, wherein the cancer is pancreatic cancer, prostate cancer, lung cancer, melanoma, breast cancer, colon cancer, or ovarian cancer. 